Repeat expansion in a fragile X model is independent of double strand break repair mediated by Pol θ, RAD52, RAD54 or RAD54B.
Academic Journal
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Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
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Hayward BE;Kim GY;Miller CJ;McCann C;Lowery MG;Wood RD;Usdin K
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Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
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Microsatellite instability is responsible for the human repeat expansion diseases (RED...
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Repeat expansion in a fragile X model is independent of double strand break repair mediated by Pol θ, RAD52, RAD54 or RAD54B.
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Microsatellite instability is responsible for the human repeat expansion diseases (REDs). The mutagenic process differs from classical cancer-associated microsatellite instability (MSI) in that it requires the mismatch repair proteins that normally protect against MSI. LIG4, an enzyme essential for non-homologous end-joining (NHEJ), the major pathway for double-strand break repair (DSBR) in mammalian cells, protects against expansion in mouse models. Thus, NHEJ may compete with the expansion pathway for access to a common intermediate. This raises the possibility that expansion involves an NHEJ-independent form of DSBR. Pol θ, a polymerase involved in the theta-mediated end joining (TMEJ) DSBR pathway, has been proposed to play a role in repeat expansion. Here we examine the effect of the loss of Pol θ on expansion in FXD mouse embryonic stem cells (mESCs), along with the effects of mutations in Rad52, Rad54l and Rad54b, genes important for multiple DSBR pathways. None of these mutations significantly affected repeat expansion. These observations put major constraints on what pathways are likely to drive expansion. Together with our previous demonstration of the protective effect of nucleases like EXO1 and FAN1, and the importance of Pol β, they suggest a plausible model for late steps in the expansion process.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Subject terms:
Animals - Mice - Nuclear Proteins genetics - Nuclear Proteins metabolism - DNA-Binding Proteins genetics - DNA-Binding Proteins metabolism - DNA Repair - Mouse Embryonic Stem Cells metabolism - Humans - Disease Models, Animal - DNA-Directed DNA Polymerase metabolism - DNA-Directed DNA Polymerase genetics - DNA Polymerase theta - DNA Breaks, Double-Stranded - DNA End-Joining Repair - Rad52 DNA Repair and Recombination Protein metabolism - Rad52 DNA Repair and Recombination Protein genetics - DNA Helicases genetics - DNA Helicases metabolismContent provider:
MEDLINE
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Molecular mechanisms for repair of DNA / edited by Philip C. Hanawalt and Richard B. Setlow.
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1975
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1975
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Particulate hexavalent chromium inhibits global transcription of genes in DNA repair pathways, particularly targeting homologous recombination repair , base excision repair ,...
Academic Journal
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9422688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3336 (Electronic) Linking ISSN: 03043894 NLM ISO Abbreviation: J Hazard Mater Subsets: MEDLINE
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Meaza I;Cahill CR;Speer RM;Kouokam JC;Wise JP Sr
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9422688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3336 (Electronic) Linking ISSN: 03043894 NLM ISO Abbreviation: J Hazard Mater Subsets: MEDLINE
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Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread exposure. How ...
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Particulate hexavalent chromium inhibits global transcription of genes in DNA repair pathways, particularly targeting homologous recombination repair , base excision repair ,...
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9422688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3336 (Electronic) Linking ISSN: 03043894 NLM ISO Abbreviation: J Hazard Mater Subsets: MEDLINE
Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread exposure. How Cr(VI) causes cancer is poorly understood, but chromosome instability plays a central role. Inhibition of DNA repair pathways leads to chromosome instability; however, despite the importance of these pathways in the mechanism of Cr(VI)-induced lung carcinogenesis, there are no data considering in-depth analysis on the transcriptional changes of genes involved in them. This study characterized the global transcriptional changes of mRNA expression after Cr(VI) exposure focusing on DNA repair pathways. The repair pathways considered included homologous recombination repair , non-homologous end joining, microhomology-directed end-joining, single strand annealing, mismatch repair , base excision repair , nucleotide excision repair and crosslink repair . Normal human lung fibroblast cells were exposed to increasing zinc chromate concentrations for 24, 72 or 120 h then RNA was extracted and sequenced. Our results indicate Cr(VI) causes differential expression of genes in lung cancer pathways and downregulates expression of some genes in all 8 DNA repair pathways. Homologous recombination repair , mismatch repair , base excision repair and microhomology-directed end-joining were the most affected pathways. This study provides a critical in-depth analysis of the effects of Cr(VI) on DNA repair pathways and contributes new insights into the mechanism of Cr(VI)-carcinogenesis.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Subject terms:
Humans - Transcription, Genetic drug effects - Chromates toxicity - DNA Mismatch Repair drug effects - DNA End-Joining Repair drug effects - Cell Line - Fibroblasts drug effects - Fibroblasts metabolism - RNA, Messenger genetics - RNA, Messenger metabolism - Recombinational DNA Repair drug effects - Excision Repair - Zinc Compounds - Chromium toxicity - DNA Repair drug effectsContent provider:
MEDLINE
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DNA repair and mutagenesis / Errol C. Friedberg, Graham C. Walker, Wolfram Siede.
Book
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1995
Book
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1995
Available at Dewey Collection (574.87328 F912d)
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Host repair polymorphisms and H. pylori genes in gastric disease outcomes: Who are the guardian and villains?
Academic Journal
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Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 7706761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0038 (Electronic) Linking ISSN: 03781119 NLM ISO Abbreviation: Gene Subsets: MEDLINE
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Maria de Oliveira Barboza M;Ferreira da Costa R;Paulo Por Deus Gomes J;Mári...
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Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 7706761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0038 (Electronic) Linking ISSN: 03781119 NLM ISO Abbreviation: Gene Subsets: MEDLINE
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Gastric cancer (GC) is the fourth-leading cause of cancer-related mortality. The intes...
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Host repair polymorphisms and H. pylori genes in gastric disease outcomes: Who are the guardian and villains?
Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 7706761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0038 (Electronic) Linking ISSN: 03781119 NLM ISO Abbreviation: Gene Subsets: MEDLINE
Gastric cancer (GC) is the fourth-leading cause of cancer-related mortality. The intestinal subtype of GC comes after the cascade of Correa, presenting H. pylori infection as the major etiological factor. One of the main mechanisms proposed for the progression from a more benign gastric lesion to cancer is DNA damage caused by chronic inflammation. Polymorphisms in DNA repair genes can lead to an imbalance of host DNA damage and repair , contributing to the development of GC. From there, we evaluated the risk of polymorphisms in DNA repair system genes in progressive gastric diseases and their association with the H. pylori genotype. This study included 504 patients from two public hospitals in Brazil's north and northeast regions. The samples were classified into active and inactive gastritis, metaplasia, and GC. Polymorphisms in the DNA repair genes MLH1-93G > A, APE1 2197 T > G, XRCC1 28,152 G > A, MGMT 533 A > G, and XRCC3 18,067C > T were investigated by RFLP-PCR and H. pylori genotype by PCR. Statistical analyses were conducted using EPINFO 7.0., SNPSTAT, and CART software. The XRCC1 (GA) polymorphic allele stood out because it was associated with a lower risk of more severe gastric disease progression. Haplotypes of XRCC1 (GA) associated with some genotypes of MGMT, XRCC3, MLH1, and APE1 also showed protection against the progression of gastric diseases. XRCC3 (CT) showed a decreased risk of gastric disease progression in women, while a risk 1.3x to GC was observed in the MLH1 (A) polymorphic allele. The interaction between H. pylori genes and the host showed that the H. pylori cagE gene was the most important virulence factor associated with a worse clinical outcome, even overlapping with the XRCC1 polymorphism, where the MLH1 polymorphism response varied according to vacA alleles. Our results show the relevance of XRCC1 G > A for genome integrity, sex influence, and interaction between H. pylori virulence factors and XRCC1 and MLH1 genotypes for gastric lesion outcomes in Brazilian populations.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Subject terms:
Humans - Female - Male - Middle Aged - X-ray Repair Cross Complementing Protein 1 genetics - Polymorphism, Single Nucleotide - Adult - DNA Repair Enzymes genetics - DNA-Binding Proteins genetics - Aged - MutL Protein Homolog 1 genetics - Tumor Suppressor Proteins genetics - DNA Modification Methylases genetics - Genetic Predisposition to Disease - Genotype - Gastritis genetics - Gastritis microbiology - Brazil - Helicobacter pylori genetics - Helicobacter pylori pathogenicity - Helicobacter Infections genetics - Helicobacter Infections microbiology - Stomach Neoplasms genetics - Stomach Neoplasms microbiology - DNA Repair geneticsContent provider:
MEDLINE
Fixing your damaged and incorrect genes / Errol C. Friedberg, University of Texas Southwestern Medical Center, USA.
Book
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2019
Book
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2019
Available at LC Collection (QH467 .F756 2019)
Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.
Academic Journal
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101139138 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1568-7856 (Electronic) Linking ISSN: 15687856 NLM ISO Abbreviation: DNA Repair (Amst) Subsets: MEDLINE
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Trost H;Lopezcolorado FW;Merkell A;Stark JM
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101139138 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1568-7856 (Electronic) Linking ISSN: 15687856 NLM ISO Abbreviation: DNA Repair (Amst) Subsets: MEDLINE
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Repeat-mediated deletions (RMDs) are a type of deletion rearrangement that utilizes tw...
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Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101139138 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1568-7856 (Electronic) Linking ISSN: 15687856 NLM ISO Abbreviation: DNA Repair (Amst) Subsets: MEDLINE
Repeat-mediated deletions (RMDs) are a type of deletion rearrangement that utilizes two repetitive elements to bridge a DNA double-strand break (DSB) that leads to loss of the intervening sequence and one of the repeats. Sequence divergence between repeats causes RMD suppression and indeed this divergence must be resolved in the RMD products. The mismatch repair factor, MLH1, was shown to be critical for both RMD suppression and a polarity of sequence divergence resolution in RMDs. Here, we sought to study the interrelationship between these two aspects of RMD regulation (i.e., RMD suppression and polar divergence resolution), by examining several mutants of MLH1 and its binding partner PMS2. To begin with, we show that PMS2 is also critical for both RMD suppression and polar resolution of sequence divergence in RMD products. Then, with six mutants of the MLH1-PMS2 heterodimer, we found several different patterns: three mutants showed defects in both functions, one mutant showed loss of RMD suppression but not polar divergence resolution, whereas another mutant showed the opposite, and finally one mutant showed loss of RMD suppression but had a complex effect on polar divergence resolution. These findings indicate that RMD suppression vs. polar resolution of sequence divergence are distinct functions of MLH1-PMS2.
Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Subject terms:
Adenosine Triphosphatases metabolism - Adenosine Triphosphatases genetics - Saccharomyces cerevisiae Proteins metabolism - Saccharomyces cerevisiae Proteins genetics - DNA Repair Enzymes metabolism - DNA Repair Enzymes genetics - Repetitive Sequences, Nucleic Acid - Saccharomyces cerevisiae genetics - Saccharomyces cerevisiae metabolism - Sequence Deletion - DNA Breaks, Double-Stranded - MutL Protein Homolog 1 metabolism - MutL Protein Homolog 1 genetics - Mismatch Repair Endonuclease PMS2 metabolism - Mismatch Repair Endonuclease PMS2 genetics - Adaptor Proteins, Signal Transducing metabolism - Adaptor Proteins, Signal Transducing genetics - DNA-Binding Proteins metabolism - DNA-Binding Proteins genetics - Nuclear Proteins metabolism - Nuclear Proteins geneticsContent provider:
MEDLINE
The Structure and replication of genetic material / edited by David M. Prescott, Lester Goldstein.
Book
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1978
Book
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1978
Available at Dewey Collection (574.87 C33 v.2)
Single-molecule studies of repair proteins in base excision repair .
Academic Journal
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Publisher: Korean Society for Biochemistry and Molecular Biology Country of Publication: Korea (South) NLM ID: 101465334 Publication Model: Print Cited Medium: Internet ISSN: 1976-670X (Electronic) Linking ISSN: 19766696 NLM ISO Abbreviation: BMB Rep Subsets: MEDLINE
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Lee D;Lee G
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Publisher: Korean Society for Biochemistry and Molecular Biology Country of Publication: Korea (South) NLM ID: 101465334 Publication Model: Print Cited Medium: Internet ISSN: 1976-670X (Electronic) Linking ISSN: 19766696 NLM ISO Abbreviation: BMB Rep Subsets: MEDLINE
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Base excision repair (BER) is an essential cellular mechanism that repairs small, non-...
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Single-molecule studies of repair proteins in base excision repair .
Publisher: Korean Society for Biochemistry and Molecular Biology Country of Publication: Korea (South) NLM ID: 101465334 Publication Model: Print Cited Medium: Internet ISSN: 1976-670X (Electronic) Linking ISSN: 19766696 NLM ISO Abbreviation: BMB Rep Subsets: MEDLINE
Base excision repair (BER) is an essential cellular mechanism that repairs small, non-helix-distorting base lesions in DNA , resulting from oxidative damage, alkylation, deamination, or hydrolysis. This review highlights recent advances in understanding the molecular mechanisms of BER enzymes through single-molecule studies. We discuss the roles of DNA glycosylases in lesion recognition and excision, with a focus on facilitated diffusion mechanisms such as sliding and hopping that enable efficient genome scanning. The dynamics of apurinic/apyrimidinic endonucleases, especially the coordination between APE1 and DNA polymerase β (Pol β), are explored to demonstrate their crucial roles in processing abasic sites. The review further explores the short-patch and long-patch BER pathways, emphasizing the activities of Pol β, XRCC1, PARP1, FEN1, and PCNA in supporting repair synthesis and ligation. Additionally, we highlight the emerging role of UV-DDB as a general damage sensor in BER, extending its recognized function beyond nucleotide excision repair . Single-molecule techniques have been instrumental in uncovering the complex interactions and mechanisms of BER proteins, offering unprecedented insights that could guide future therapeutic strategies for maintaining genomic stability. [BMB Reports 2025; 58(1): 17-23].
Subject terms:
Humans - DNA Damage - X-ray Repair Cross Complementing Protein 1 metabolism - DNA Glycosylases metabolism - Flap Endonucleases metabolism - DNA metabolism - Proliferating Cell Nuclear Antigen metabolism - Excision Repair - DNA Repair - DNA Polymerase beta metabolism - DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism - Single Molecule Imaging methodsContent provider:
MEDLINE
Dynamic interplay of cNHEJ and MMEJ pathways of DNA double-strand break repair during embryonic development in zebrafish.
Academic Journal
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Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
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Carrara M;Gaillard AL;Brion A;Duvernois-Berthet E;Giovannangeli C;Concordet...
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Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
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Double strand breaks (DSBs) are the most deleterious DNA lesions as they frequently re...
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Dynamic interplay of cNHEJ and MMEJ pathways of DNA double-strand break repair during embryonic development in zebrafish.
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
Double strand breaks (DSBs) are the most deleterious DNA lesions as they frequently result in mutations when repaired by canonical non homologous end-joining (cNHEJ) and microhomology-mediated end-joining (MMEJ). Here, we investigated the relative importance of cNHEJ and MMEJ pathways during zebrafish embryonic development. We have analyzed the expression of cNHEJ and MMEJ related genes and found that it was dynamic during development and often become increased in specific tissues. We showed that inactivation of nuclear DNA ligase 3 (nLig3) or DNA polymerase theta (Polθ), two key MMEJ factors, did not affect zebrafish development but sensitized embryos to ionizing radiations and that deficiency of Polθ, but not nLig3, profoundly alters the mutation spectrum induced during repair of Cas9-mediated DSBs. By contrast, inactivation of DNA ligase 4, required for cNHEJ, did not seem to sensitize embryos to ionizing radiations nor to affect repair of Cas9-mediated DSBs but resulted in important larval growth defects. Our study underscores the dynamic and context-dependent roles of cNHEJ and MMEJ pathways during zebrafish development, highlighting their differential requirements across developmental stages and in response to genotoxic stress.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2025. The Author(s).)
Subject terms:
Animals - Zebrafish Proteins genetics - Zebrafish Proteins metabolism - DNA Polymerase theta - DNA-Directed DNA Polymerase metabolism - DNA-Directed DNA Polymerase genetics - DNA Repair - Zebrafish genetics - Zebrafish embryology - DNA Breaks, Double-Stranded radiation effects - Embryonic Development genetics - Embryonic Development radiation effects - DNA End-Joining RepairContent provider:
MEDLINE
SRPKs Homolog Dsk1 Regulates Homologous Recombination Repair in Schizosaccharomyces pombe.
Academic Journal
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Publisher: Blackwell Science Ltd Country of Publication: England NLM ID: 9607379 Publication Model: Print Cited Medium: Internet ISSN: 1365-2443 (Electronic) Linking ISSN: 13569597 NLM ISO Abbreviation: Genes Cells Subsets: MEDLINE
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Lu G;Tang Z;Wu M;Liu L;Opoku M;Bian K;Ruan R;Shang J;Liu J;Feng G
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Publisher: Blackwell Science Ltd Country of Publication: England NLM ID: 9607379 Publication Model: Print Cited Medium: Internet ISSN: 1365-2443 (Electronic) Linking ISSN: 13569597 NLM ISO Abbreviation: Genes Cells Subsets: MEDLINE
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Serine-arginine protein kinases (SRPKs) play important roles in diverse biological pro...
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SRPKs Homolog Dsk1 Regulates Homologous Recombination Repair in Schizosaccharomyces pombe.
Publisher: Blackwell Science Ltd Country of Publication: England NLM ID: 9607379 Publication Model: Print Cited Medium: Internet ISSN: 1365-2443 (Electronic) Linking ISSN: 13569597 NLM ISO Abbreviation: Genes Cells Subsets: MEDLINE
Serine-arginine protein kinases (SRPKs) play important roles in diverse biological processes such as alternative splicing and cell cycle. However, the functions of SRPKs in DNA damage response remain unclear. Here we characterized the function of SRPKs homolog Dsk1 in regulating DNA repair in the fission yeast Schizosaccharomyces pombe. We demonstrated that Dsk1 defective mutants of loss of the gene, spacer domain, and kinase activity as well as its overexpression mutant exhibited sensitivities of replication stress. Genetic analysis revealed that the loss of dsk1 + compromised the efficiency of homologous recombination (HR) repair , and Dsk1 was probably involved in the Rad52- and Rad51-dependent HR repair pathways. Interestingly, Dsk1 translocated into the nucleus upon replication stress and directly interacted with Rad51-mediator Rad52 and phosphorylated Rad52-Ser365 residue. The Rad52-Ser365 phosphorylation-defective mutant was slightly sensitive to replication stress, and the phosphorylation-mimicking mutants exhibited more sensitivities, which were partially correlated with phenotypes of the loss- and gain-of-function of dsk1 + . This study uncovers a potential HR repair regulator Dsk1 in response to replication stress and implies that its homolog SRPKs may have the conserved targets and functions in higher eukaryotes.
(© 2025 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)
(© 2025 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)
Subject terms:
Phosphorylation - Rad52 DNA Repair and Recombination Protein metabolism - Rad52 DNA Repair and Recombination Protein genetics - Protein Serine-Threonine Kinases metabolism - Protein Serine-Threonine Kinases genetics - DNA Replication - DNA Damage - Rad51 Recombinase metabolism - Rad51 Recombinase genetics - DNA-Binding Proteins - Schizosaccharomyces genetics - Schizosaccharomyces metabolism - Schizosaccharomyces pombe Proteins metabolism - Schizosaccharomyces pombe Proteins genetics - Recombinational DNA RepairContent provider:
MEDLINE
XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.
Academic Journal
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Lin X;Leung KSK;Wolfe KF;Call N;Bhandari SK;Huang X;Lee BJ;Tomkinson AE;Zha...
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Poly-ADP-ribose polymerases 1 and 2 (PARP1 and 2) are critical sensors of DNA-strand b...
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XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to DNA damage sites.
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
Poly-ADP-ribose polymerases 1 and 2 (PARP1 and 2) are critical sensors of DNA -strand breaks and targets for cancer therapy. Upon DNA damage, PARP1 and 2 synthesize poly-ADP-ribose (PAR) chains on themselves and other substrates, facilitating DNA single-strand break repair by recruiting PAR-binding DNA repair factors, including X-ray repair cross-complementing group 1 (XRCC1) and aprataxin and polynucleotide kinase phosphatase-like factor (APLF). While diverse DNA lesions activate PARP1, PARP2 is selectively activated by 5' phosphorylated nicks. They function independently and compensate for each other. Previous studies suggest that PARP1 and its PAR chains act upstream to recruit PARP2 to DNA damage sites. Here, we report that the scaffold protein XRCC1 mediates PARP1- and PAR-dependent recruitment of PARP2 to damage sites. XRCC1-deficiency causes hyperactivation of PARP1 while attenuating micro-irradiation-induced PARP2 foci. Mechanistically, the BRCT1 domain of XRCC1 binds to PAR, while its BRCT2 domain interacts with the PARP2 catalytic domain independently of the PARP2 enzymatic activity and the LIG3 BRCT domain via residues D575 and Y576. This mode of PARP2 enrichment is important for the recruitment of certain PAR-binding proteins, such as APLF, but dispensable for others, such as the XRCC1-BRCT1 domain. These findings highlight the distinct role of PARP1 and PARP2 in PAR synthesis and uncover unexpected hierarchical roles of PARP1 and XRCC1 upstream of PARP2.
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Subject terms:
Animals - Humans - Mice - Poly Adenosine Diphosphate Ribose metabolism - DNA Repair - DNA Breaks, Single-Stranded - X-ray Repair Cross Complementing Protein 1 metabolism - X-ray Repair Cross Complementing Protein 1 genetics - Poly (ADP-Ribose) Polymerase-1 metabolism - Poly (ADP-Ribose) Polymerase-1 genetics - Poly(ADP-ribose) Polymerases metabolism - Poly(ADP-ribose) Polymerases genetics - DNA Damage - DNA-Binding Proteins metabolism - DNA-Binding Proteins geneticsContent provider:
MEDLINE
Evaluation of T-cell repertoire by flow cytometric analysis in primary immunodeficiencies with DNA repair defects.
Academic Journal
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Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0323767 Publication Model: Print Cited Medium: Internet ISSN: 1365-3083 (Electronic) Linking ISSN: 03009475 NLM ISO Abbreviation: Scand J Immunol Subsets: MEDLINE
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Karaaslan BG;Demirkale ZH;Turan I;Aydemir S;Meric Z;Taskin Z;Kilinc OC;Burt...
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Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0323767 Publication Model: Print Cited Medium: Internet ISSN: 1365-3083 (Electronic) Linking ISSN: 03009475 NLM ISO Abbreviation: Scand J Immunol Subsets: MEDLINE
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The group of patients with DNA-repair-defects increases susceptibility to infections d...
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Evaluation of T-cell repertoire by flow cytometric analysis in primary immunodeficiencies with DNA repair defects.
Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0323767 Publication Model: Print Cited Medium: Internet ISSN: 1365-3083 (Electronic) Linking ISSN: 03009475 NLM ISO Abbreviation: Scand J Immunol Subsets: MEDLINE
The group of patients with DNA -repair -defects increases susceptibility to infections due to impaired repertoire diversity. In this context, we aimed to investigate the TCRvβ-repertoire by flow cytometric analysis and its correlation with clinical entities in a group of IEI patients with DNA repair defects. Peripheral lymphocyte subset and TCRvβ-repertoire analyses were performed by flow cytometric analysis. The aim was to explore the changing TCR-Vβ-repertoire that can predict some clinical entities by investigating the repertoire using flow-cytometric-analysis-based TCR-Vβ and its interaction with clinical entities in a group of IEI patients with DNA repair defects. TCR-repertoire of the patients with DNA -repair -defects and healthy controls was analysed with flow-cytometer. The potential of flow-cytometric analysis of the TCR repertoire as a practical and easily accessible clinical prediction method was investigated. Thirty-nine-IEI patients with DNA -repair -defects and 15 age-matched healthy-controls were included in this study. Peripheral lymphocyte subset and TCR-Vβ repertoire analyses were performed by flow cytometry. Compared to the control group, 9 out of 24 clones (37.5%) exhibited a statistically significant reduction, while only 3 clones showed a statistically significant increase (p < 0.05). Preferential use of vβ-genes was associated with some clinical entities. Lower TCR-vβ-9 and TCR-vβ23, higher TCR-vβ7.2 were found in the patients with pneumonia (n = 13) (p = 0.018, p = 0.044 p = 0.032). AT patients with pneumonia had lower TCR-vβ-9 clone than patients without pneumonia (p = 0.008). Skewed proliferation of most TCR-vβ clones was seen DNA -repair -defects, especially AT. In addition, this study showed that preferential use of TCR-vβ genes could be predictive for some clinical entities.
(© 2025 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)
(© 2025 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)
Subject terms:
Humans - Male - Female - Child - Child, Preschool - Adolescent - Adult - Infant - T-Lymphocytes immunology - Young Adult - DNA Repair-Deficiency Disorders genetics - DNA Repair-Deficiency Disorders immunology - Middle Aged - Flow Cytometry methods - Receptors, Antigen, T-Cell, alpha-beta genetics - DNA Repair geneticsContent provider:
MEDLINE
Nucleotide Excision Repair : Insights into Canonical and Emerging Functions of the Transcription/DNA Repair Factor TFIIH.
Academic Journal
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Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
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Zachayus A;Loup-Forest J;Cura V;Poterszman A
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Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
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Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism tha...
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Nucleotide Excision Repair : Insights into Canonical and Emerging Functions of the Transcription/DNA Repair Factor TFIIH.
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key player of the NER pathway in eukaryotes. This 10-subunit multiprotein complex notably verifies the presence of a lesion and opens the DNA around the damage via its XPB and XPD subunits, two proteins identified in patients suffering from Xeroderma Pigmentosum syndrome. Isolated as a class II gene transcription factor in the late 1980s, TFIIH is a prototypic molecular machine that plays an essential role in both DNA repair and transcription initiation and harbors a DNA helicase, a DNA translocase, and kinase activity. More recently, TFIIH subunits have been identified as participating in other cellular processes, including chromosome segregation during mitosis, maintenance of mitochondrial DNA integrity, and telomere replication.
Subject terms:
Humans - DNA Damage genetics - Xeroderma Pigmentosum genetics - Xeroderma Pigmentosum metabolism - Xeroderma Pigmentosum Group D Protein genetics - Xeroderma Pigmentosum Group D Protein metabolism - Transcription, Genetic - DNA Helicases genetics - DNA Helicases metabolism - Animals - Excision Repair - DNA Repair - Transcription Factor TFIIH metabolism - Transcription Factor TFIIH geneticsContent provider:
MEDLINE
Transcription factors, nucleotide excision repair , and cancer: A review of molecular interplay.
Academic Journal
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9508482 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5875 (Electronic) Linking ISSN: 13572725 NLM ISO Abbreviation: Int J Biochem Cell Biol Subsets: MEDLINE
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Guneri-Sozeri PY;Adebali O
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Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9508482 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5875 (Electronic) Linking ISSN: 13572725 NLM ISO Abbreviation: Int J Biochem Cell Biol Subsets: MEDLINE
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Bulky DNA adducts are mostly formed by external factors such as UV irradiation, smokin...
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Transcription factors, nucleotide excision repair , and cancer: A review of molecular interplay.
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9508482 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-5875 (Electronic) Linking ISSN: 13572725 NLM ISO Abbreviation: Int J Biochem Cell Biol Subsets: MEDLINE
Bulky DNA adducts are mostly formed by external factors such as UV irradiation, smoking or treatment with DNA crosslinking agents. If such DNA adducts are not removed by nucleotide excision repair , they can lead to formation of driver mutations that contribute to cancer formation. Transcription factors (TFs) may critically affect both DNA adduct formation and repair efficiency at the binding site to DNA . For example, "hotspot" mutations in melanoma coincide with UV-induced accumulated cyclobutane pyrimidine dimer (CPD) adducts and/or inhibited repair at the binding sites of some TFs. Similarly, anticancer treatment with DNA cross-linkers may additionally generate DNA adducts leading to secondary mutations and the formation of malignant subclones. In addition, some TFs are overexpressed in response to UV irradiation or chemotherapeutic treatment, activating oncogenic and anti-oncogenic pathways independently of nucleotide excision repair itself. This review focuses on the interplay between TFs and nucleotide excision repair during cancer development and progression.
Competing Interests: Declaration of Competing Interest The authors declare no competing interests.
(Copyright © 2024. Published by Elsevier Ltd.)
Competing Interests: Declaration of Competing Interest The authors declare no competing interests.
(Copyright © 2024. Published by Elsevier Ltd.)
Subject terms:
Humans - Animals - DNA Adducts metabolism - DNA Adducts genetics - Excision Repair - DNA Repair genetics - Neoplasms genetics - Neoplasms metabolism - Neoplasms pathology - Transcription Factors metabolism - Transcription Factors geneticsContent provider:
MEDLINE
Particulate hexavalent chromium exposure induces DNA double-strand breaks and inhibits homologous recombination repair in rat and human lung tissues.
Academic Journal
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Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 0320657 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1298 (Electronic) Linking ISSN: 00456535 NLM ISO Abbreviation: Chemosphere Subsets: MEDLINE
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Lu H;Wise SS;Toyoda JH;Speer RM;Croom-Perez TJ;Meaza I;Kouokam JC;Wise JL;H...
Academic Journal
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Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 0320657 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1298 (Electronic) Linking ISSN: 00456535 NLM ISO Abbreviation: Chemosphere Subsets: MEDLINE
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Lung cancer is an important human health concern because of its high mortality rate, w...
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Particulate hexavalent chromium exposure induces DNA double-strand breaks and inhibits homologous recombination repair in rat and human lung tissues.
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 0320657 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1298 (Electronic) Linking ISSN: 00456535 NLM ISO Abbreviation: Chemosphere Subsets: MEDLINE
Lung cancer is an important human health concern because of its high mortality rate, with many cases caused by environmental chemicals other than tobacco. Particulate hexavalent chromium [Cr(VI)] is a well-established human lung carcinogen, but how Cr(VI) induces lung cancer is poorly understood. Chromosome instability, a hallmark of lung cancer, is considered a major driving factor in Cr(VI)-induced lung cancer. Our previous studies in cultured human lung cells showed that particulate Cr(VI) induces DNA double-strand breaks during the late S and G2 phases of the cell cycle, which are repaired by homologous recombination, one of the main repair pathways of DNA double-strand breaks. Our previous data showed that prolonged exposure to Cr(VI) inhibits homologous recombination repair by targeting RAD51, a key protein that mediates homologous recombination. Therefore, particulate Cr(VI)-induced DNA damage combined with failure of DNA repair can lead to chromosome instability. In this study we translated these results to rat lung tissue and lung tumor tissue from Cr(VI)-exposed workers. Wistar rats were exposed to zinc chromate in a saline solution or saline alone by oropharyngeal aspiration with a single dose repeated weekly for 90 days. We observed DNA double-strand breaks increased in a concentration-dependent manner, but homologous recombination repair decreased in rat lungs after 90 days of exposure. Notably, these effects were more pronounced in bronchioles than alveoli. We also considered these effects in Cr(VI)-associated human lung tumors and observed increased DNA double-strand breaks and reduced RAD51 levels in lung tumor tissue compared with adjacent normal lung tissue. Thus, Cr(VI)-induced induction of DNA double-strand breaks, and inhibition of homologous recombination repair translates from cultured cells to experimental animals, normal lung tissue adjacent to the tumor, and Cr(VI)-associated human lung tumors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Subject terms:
Animals - Rats - Humans - Chromates toxicity - Male - Zinc Compounds toxicity - DNA Repair drug effects - Rad51 Recombinase metabolism - DNA Breaks, Double-Stranded drug effects - Chromium toxicity - Lung drug effects - Lung pathology - Rats, Wistar - Lung Neoplasms chemically induced - Recombinational DNA Repair drug effectsContent provider:
MEDLINE
Cockayne syndrome B protein is implicated in transcription and associated chromatin dynamics in homeostatic and genotoxic conditions.
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Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE
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Liakos A;Ntakou-Zamplara KZ;Angelova N;Konstantopoulos D;Synacheri AC;Spyro...
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Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE
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The integrity of the actively transcribed genome against helix-distorting DNA lesions ...
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Cockayne syndrome B protein is implicated in transcription and associated chromatin dynamics in homeostatic and genotoxic conditions.
Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE
The integrity of the actively transcribed genome against helix-distorting DNA lesions relies on a multilayered cellular response that enhances Transcription-Coupled Nucleotide Excision Repair (TC-NER). When defective, TC-NER is causatively associated with Cockayne-Syndrome (CS), a rare severe human progeroid disorder. Although the presence of unresolved transcription-blocking lesions is considered a driver of the aging process, the molecular features of the transcription-driven response to genotoxic stress in CS-B cells remain largely unknown. Here, an in-depth view of the transcriptional and associated chromatin dynamics that occur in CS-B cells illuminates the role of CSB therein. By employing high-throughput genome-wide approaches, we observed that absence of a functional CSB protein results in a delay in transcription progression, more positioned +1 nucleosomes, and less dynamic chromatin structure, compared to normal cells. We found that early after exposure to UV, CS-B cells released RNA polymerase II (RNAPII) from promoter-proximal pause sites into elongation. However, the magnitude of this response and the progression of RNAPII were reduced compared to normal counterparts. Notably, we detected increased post-UV retainment of unprocessed nascent RNA transcripts and chromatin-associated elongating RNAPII molecules. Contrary to the prevailing models, we found that transcription initiation is operational in CS-B fibroblasts early after UV and that chromatin accessibility showed a marginal increase. Our study provides robust evidence for the role of CSB in shaping the transcription and chromatin landscape both in homeostasis and in response to genotoxic insults, which is independent of its known role in TC-NER, and which may underlie major aspects of the CS phenotype.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Subject terms:
Humans - RNA Polymerase II metabolism - DNA Repair - Ultraviolet Rays - Poly-ADP-Ribose Binding Proteins metabolism - Poly-ADP-Ribose Binding Proteins genetics - DNA Repair Enzymes metabolism - DNA Repair Enzymes genetics - DNA Helicases metabolism - DNA Helicases genetics - Chromatin metabolism - Chromatin genetics - Cockayne Syndrome genetics - Cockayne Syndrome metabolism - Transcription, Genetic - DNA Damage - HomeostasisContent provider:
MEDLINE
Faulty Gap Filling in Nucleotide Excision Repair Leads to Double-Strand Break Formation in Senescent Cells.
Academic Journal
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Publisher: Elsevier Country of Publication: United States NLM ID: 0426720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1747 (Electronic) Linking ISSN: 0022202X NLM ISO Abbreviation: J Invest Dermatol Subsets: MEDLINE
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Suzuki T;Komaki Y;Amano M;Ando S;Shobu K;Ibuki Y
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Publisher: Elsevier Country of Publication: United States NLM ID: 0426720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1747 (Electronic) Linking ISSN: 0022202X NLM ISO Abbreviation: J Invest Dermatol Subsets: MEDLINE
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The change of repair efficiency of UV-induced pyrimidine dimers due to aging was exami...
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Faulty Gap Filling in Nucleotide Excision Repair Leads to Double-Strand Break Formation in Senescent Cells.
Publisher: Elsevier Country of Publication: United States NLM ID: 0426720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1747 (Electronic) Linking ISSN: 0022202X NLM ISO Abbreviation: J Invest Dermatol Subsets: MEDLINE
The change of repair efficiency of UV-induced pyrimidine dimers due to aging was examined in replicatively senesced fibroblasts. The fibroblasts with repeated passages showed the characteristics of cellular senescence, including irreversible cell cycle arrest, elevated β-galactosidase activity, and senescence-associated secretory phenotype. The incision efficiency of oligonucleotide containing UV lesions was similar regardless of cell doubling levels, but the gap filling process was impaired in replicatively senescent cells. The releases of xeroderma pigmentosum group G, proliferating cell nuclear antigen, and replication protein A from damaged sites were delayed, which might have disturbed the DNA polymerase progression. The persistent single-stranded DNA was likely converted to double-strand breaks, leading to ataxia telangiectasia-mutated phosphorylation and 53BP1 foci formation. Phosphorylated histone H2AX (γ-H2AX) induction mainly occurred in G1 phase in senescent cells, not in S phase such as in normal cells, indicating that replication stress-independent double-strand breaks might be formed. MRE11 having nuclease activity accumulated to damaged sites at early time point after UV irradiation but not released in senescent cells. The pharmacological studies using specific inhibitors for the nuclease activity suggested that MRE11 contributed to the enlargement of single-stranded DNA gap, facilitating the double-strand break formation.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Subject terms:
Humans - Cells, Cultured - Pyrimidine Dimers metabolism - Pyrimidine Dimers genetics - Proliferating Cell Nuclear Antigen metabolism - Tumor Suppressor p53-Binding Protein 1 metabolism - Tumor Suppressor p53-Binding Protein 1 genetics - Phosphorylation - Ataxia Telangiectasia Mutated Proteins metabolism - Ataxia Telangiectasia Mutated Proteins genetics - DNA, Single-Stranded metabolism - DNA, Single-Stranded genetics - Excision Repair - Cellular Senescence radiation effects - DNA Repair - Fibroblasts metabolism - Fibroblasts radiation effects - Ultraviolet Rays adverse effects - Histones metabolism - DNA Breaks, Double-Stranded radiation effects - DNA-Binding Proteins metabolism - DNA-Binding Proteins genetics - MRE11 Homologue Protein metabolism - MRE11 Homologue Protein geneticsContent provider:
MEDLINE
Comparative Studies on Bulky DNA Damage Binding by Nucleotide Excision Repair Proteins Using Surface Plasmon Resonance, Differential Scanning Fluorometry, and DNase I Footprinting.
Academic Journal
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Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
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Cai A;LaVigne KL;Crisalli AM;Delaney S;Min JH;Cho BP
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Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
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Nucleotide excision repair is a crucial cellular mechanism that ensures genomic stabil...
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Comparative Studies on Bulky DNA Damage Binding by Nucleotide Excision Repair Proteins Using Surface Plasmon Resonance, Differential Scanning Fluorometry, and DNase I Footprinting.
Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE
Nucleotide excision repair is a crucial cellular mechanism that ensures genomic stability, thereby preventing mutations that can lead to cancer. The human XPC and its yeast ortholog Rad4 protein complexes are central to this process and were the focus of the study. We used surface plasmon resonance and differential scanning fluorimetry to study the binding characteristics of XPC and Rad4 when bound to the bulky cluster di-FAAF-containing 55-mer duplex DNA . Our findings revealed that XPC binds 10 times more significant affinity to control and di-FAAF-modified DNA than Rad4 with greater protein-DNA interactions. Differential scanning fluorimetry indicates that Rad4 causes comparatively more significant conformational changes upon complexation with the damaged DNA . We conducted DNase I footprinting of the Rad4/DNA complex for the first time by determining the regions protected from DNase I digestion. The DNA at the lesion is entirely resistant to digestion by DNase I in the absence of Rad4 several nucleotides to the 3'-side of the first FAAF lesion. The lack of DNase I cleavage at the lesions did not change upon adding Rad4. However, in the presence of Rad4, a footprint is observed on the 7-nucleotide region (5'-TGGTGAT-3') of the complementary strand to the 3' side of the lesion.
Subject terms:
Humans - DNA-Binding Proteins metabolism - DNA-Binding Proteins chemistry - DNA chemistry - DNA metabolism - Saccharomyces cerevisiae Proteins metabolism - Saccharomyces cerevisiae Proteins chemistry - Protein Binding - Excision Repair - Surface Plasmon Resonance - Deoxyribonuclease I metabolism - Deoxyribonuclease I chemistry - DNA Repair - DNA Damage - Fluorometry - DNA FootprintingContent provider:
MEDLINE
A mobile genetic element-derived primase-polymerase harbors multiple activities implicated in DNA replication and repair .
Academic Journal
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Fu P;Wang Y;Liu Y;Han Z;Peng Z;Liu L;Han W
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Primase-polymerases (PrimPols) play divergent functions from DNA replication to DNA re...
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A mobile genetic element-derived primase-polymerase harbors multiple activities implicated in DNA replication and repair .
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
Primase-polymerases (PrimPols) play divergent functions from DNA replication to DNA repair in all three life domains. In archaea and bacteria, numerous and diverse PPs are encoded by mobile genetic elements (MGEs) and act as the replicases for their MGEs. However, their varying activities and functions are not fully understood. In this study, we characterized a group of PrimPols that are genetically associated with prokaryotic argonaute proteins (pAgos). The pAgo-associated PrimPol (AgaPP) is likely derived from a MGE. AgaPP has polymerase and primase activities and physically interacts with a helicase encoded by its downstream gene, suggesting that they constitute a functional replication module. Further, AgaPP performs translesion DNA synthesis, terminal transfer and microhomology-mediated end joining (MMEJ), showing striking similarity to human DNA repair polymerase θ. AgaPP can promote the MMEJ repair of Cas9-induced double-stranded DNA breaks and increase cell survival post DNA damage in Escherichia coli. In addition, the MMEJ activity of AgaPP can be repurposed to assist DNA assembly in vitro. Together, the findings reveal dual role of AgaPP in both DNA replication and repair .
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Subject terms:
Humans - DNA End-Joining Repair genetics - DNA Breaks, Double-Stranded - DNA Polymerase theta - DNA Primase metabolism - DNA Primase genetics - DNA Replication - DNA-Directed DNA Polymerase metabolism - DNA-Directed DNA Polymerase genetics - Escherichia coli genetics - Interspersed Repetitive Sequences - DNA Repair geneticsContent provider:
MEDLINE
Large DNA deletions occur during DNA repair at 20-fold lower frequency for base editors and prime editors than for Cas9 nucleases.
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Publisher: Springer Nature Country of Publication: England NLM ID: 101696896 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2157-846X (Electronic) Linking ISSN: 2157846X NLM ISO Abbreviation: Nat Biomed Eng Subsets: MEDLINE
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Hwang GH;Lee SH;Oh M;Kim S;Habib O;Jang HK;Kim HS;Kim Y;Kim CH;Kim S;Bae S
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Publisher: Springer Nature Country of Publication: England NLM ID: 101696896 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2157-846X (Electronic) Linking ISSN: 2157846X NLM ISO Abbreviation: Nat Biomed Eng Subsets: MEDLINE
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When used to edit genomes, Cas9 nucleases produce targeted double-strand breaks in DNA...
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Large DNA deletions occur during DNA repair at 20-fold lower frequency for base editors and prime editors than for Cas9 nucleases.
Publisher: Springer Nature Country of Publication: England NLM ID: 101696896 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2157-846X (Electronic) Linking ISSN: 2157846X NLM ISO Abbreviation: Nat Biomed Eng Subsets: MEDLINE
When used to edit genomes, Cas9 nucleases produce targeted double-strand breaks in DNA . Subsequent DNA -repair pathways can induce large genomic deletions (larger than 100 bp), which constrains the applicability of genome editing. Here we show that Cas9-mediated double-strand breaks induce large deletions at varying frequencies in cancer cell lines, human embryonic stem cells and human primary T cells, and that most deletions are produced by two repair pathways: end resection and DNA -polymerase theta-mediated end joining. These findings required the optimization of long-range amplicon sequencing, the development of a k-mer alignment algorithm for the simultaneous analysis of large DNA deletions and small DNA alterations, and the use of CRISPR-interference screening. Despite leveraging mutated Cas9 nickases that produce single-strand breaks, base editors and prime editors also generated large deletions, yet at approximately 20-fold lower frequency than Cas9. We provide strategies for the mitigation of such deletions.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Subject terms:
Humans - Sequence Deletion genetics - DNA genetics - Cell Line, Tumor - DNA End-Joining Repair genetics - T-Lymphocytes - Endonucleases genetics - Endonucleases metabolism - Gene Editing methods - CRISPR-Cas Systems genetics - DNA Breaks, Double-Stranded - DNA Repair genetics - CRISPR-Associated Protein 9 metabolism - CRISPR-Associated Protein 9 geneticsContent provider:
MEDLINE
Mlh1-Pms1 ATPase activity is regulated distinctly by self-generated nicks and strand discrimination signals in mismatch repair .
Academic Journal
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Piscitelli JM;Witte SJ;Sakinejad YS;Manhart CM
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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In eukaryotic post-replicative mismatch repair, MutS homolog complexes detect mismatch...
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Mlh1-Pms1 ATPase activity is regulated distinctly by self-generated nicks and strand discrimination signals in mismatch repair .
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
In eukaryotic post-replicative mismatch repair , MutS homolog complexes detect mismatches and in the major eukaryotic pathway, recruit Mlh1-Pms1/MLH1-PMS2 (yeast/human) complexes, which nick the newly replicated DNA strand upon activation by the replication processivity clamp, PCNA. This incision enables mismatch removal and DNA repair . Beyond its endonuclease role, Mlh1-Pms1/MLH1-PMS2 also has ATPase activity, which genetic studies suggest is essential for mismatch repair , although its precise regulatory role on DNA remains unclear. Here, we use an ATP-binding and hydrolysis-deficient yeast Mlh1-Pms1 variant to show that ATP hydrolysis promotes disengagement from Mlh1-Pms1-generated nicks, with hydrolysis in the Mlh1 subunit driving this activity. Our data suggest that the ATPase-deficient variant becomes trapped on its own endonuclease product, suggesting a mechanistic explanation for observations in genetic experiments. Additionally, we observed that Mlh1-Pms1 selectively protects DNA from exonuclease degradation at pre-existing nicks, which may act as strand discrimination signals in mismatch repair . Together, our findings suggest that Mlh1-Pms1 exhibits distinct behaviors on its own endonuclease products versus substrates with pre-existing nicks, supporting two distinct modes of action during DNA mismatch repair .
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Subject terms:
Adenosine Triphosphate metabolism - DNA-Binding Proteins metabolism - DNA-Binding Proteins genetics - Hydrolysis - MutL Proteins metabolism - MutL Proteins genetics - DNA metabolism - DNA genetics - DNA Repair Enzymes metabolism - DNA Repair Enzymes genetics - Adaptor Proteins, Signal Transducing metabolism - Adaptor Proteins, Signal Transducing genetics - Saccharomyces cerevisiae genetics - Saccharomyces cerevisiae metabolism - Saccharomyces cerevisiae enzymology - MutL Protein Homolog 1 metabolism - MutL Protein Homolog 1 genetics - DNA Mismatch Repair - Saccharomyces cerevisiae Proteins metabolism - Saccharomyces cerevisiae Proteins genetics - Adenosine Triphosphatases metabolism - Adenosine Triphosphatases geneticsContent provider:
MEDLINE
Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.
Academic Journal
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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Hwang T;Sitko LK;Khoirunnisa R;Navarro-Aguad F;Samuel DM;Park H;Cheon B;Mut...
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Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
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In a comprehensive study to decipher the multi-layered response to the chemotherapeuti...
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Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.
Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair -deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns. We next report how distinct mutational signatures are induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas. The most toxic adduct induced by TMZ, O6-meG, is directly repaired by the O6-methylguanine-DNA methyltransferase (MGMT). In MGMT-/- cells, MMR leads to cell death and limits mutagenesis. MMR deficiency results in TMZ resistance, allowing the accumulation of ∼105 C > T substitutions corresponding to signature SBS11. Under these conditions, N3-methyladenine (3-meA), processed by base excision repair (BER), limits cell survival. Without BER, 3-meA is read through via error-prone TLS, causing T > A substitutions but not affecting survival. Blocking BER after abasic site formation results in large deletions and TMZ hypersensitization. Our findings reveal potential vulnerabilities of TMZ-resistant tumors.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Subject terms:
Humans - Antineoplastic Agents, Alkylating pharmacology - Drug Resistance, Neoplasm genetics - DNA Repair Enzymes genetics - DNA Repair Enzymes deficiency - DNA Repair Enzymes metabolism - Tumor Suppressor Proteins genetics - Tumor Suppressor Proteins deficiency - Tumor Suppressor Proteins metabolism - Cell Line - DNA Modification Methylases genetics - DNA Modification Methylases metabolism - Genome, Human - MutS Homolog 2 Protein genetics - MutS Homolog 2 Protein metabolism - Temozolomide pharmacology - DNA Mismatch Repair genetics - Whole Genome Sequencing - MutationContent provider:
MEDLINE
Transcriptomics and Proteomics Analysis of the Liver of RAD52 Knockout Mice.
Academic Journal
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Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
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Song Y;Yang L;Han Y;Li W;Wei T;Gao Y;Hu Q;Li H;Sun Y
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Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
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RAD52 plays crucial roles in several aspects of mammalian cells, including DNA double-...
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Transcriptomics and Proteomics Analysis of the Liver of RAD52 Knockout Mice.
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
RAD52 plays crucial roles in several aspects of mammalian cells, including DNA double-strand breaks repair , viral infection, cancer development, and antibody class switching. To comprehensively elucidate the role of RAD52 in maintaining genome stability and uncover additional functions of RAD52 in mammals, we performed the transcriptomics and proteomics analysis of the liver of RAD52 knockout mice. Transcriptomics analysis reveals overexpression of mitochondrial genes in the liver of RAD52 knockout (RAD52KO) mice. Proteomics analysis of RAD52KO mice shows that damage recognition proteins Cul4b and Rad23a in the process of nucleotide excision repair pathway are overexpressed. Furthermore, gene ontology and KEGG enrichment analysis (accessed on 20 November 2024) from integrated omics shows that differentially expressed genes are significantly enriched in pathways related to mitochondrial oxidative phosphorylation and nucleotide metabolism in the liver of RAD52KO mice. In addition, mRNA and protein levels of Bhmt1b are elevated in the liver of RAD52KO mice. Taken together, this study provides valuable insights into the function and mechanism of RAD52.
Subject terms:
Animals - Mice - Transcriptome - Gene Expression Profiling - DNA Repair genetics - Proteome metabolism - Mice, Knockout - Liver metabolism - Rad52 DNA Repair and Recombination Protein metabolism - Rad52 DNA Repair and Recombination Protein genetics - Proteomics methodsContent provider:
MEDLINE
SelectRepair Knockout: Efficient PTC-Free Gene Knockout Through Selectable Homology-Directed DNA Repair .
Academic Journal
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Publisher: Humana Press Country of Publication: United States NLM ID: 9214969 Publication Model: Print Cited Medium: Internet ISSN: 1940-6029 (Electronic) Linking ISSN: 10643745 NLM ISO Abbreviation: Methods Mol Biol Subsets: MEDLINE
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Cortázar MA;Jagannathan S
Academic Journal
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Publisher: Humana Press Country of Publication: United States NLM ID: 9214969 Publication Model: Print Cited Medium: Internet ISSN: 1940-6029 (Electronic) Linking ISSN: 10643745 NLM ISO Abbreviation: Methods Mol Biol Subsets: MEDLINE
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Generating nonessential gene knockouts using CRISPR/Cas9 technology is becoming increa...
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SelectRepair Knockout: Efficient PTC-Free Gene Knockout Through Selectable Homology-Directed DNA Repair .
Publisher: Humana Press Country of Publication: United States NLM ID: 9214969 Publication Model: Print Cited Medium: Internet ISSN: 1940-6029 (Electronic) Linking ISSN: 10643745 NLM ISO Abbreviation: Methods Mol Biol Subsets: MEDLINE
Generating nonessential gene knockouts using CRISPR/Cas9 technology is becoming increasingly common in biological research. In a typical workflow, the Cas9 endonuclease is used to induce a DNA double-strand break that relies on nonhomologous end-joining (NHEJ) to introduce a premature termination codon (PTC) in the target gene. The goal is to isolate clones in which the gene produces PTC-containing mRNA transcripts that are degraded via nonsense-mediated mRNA decay (NMD) to cause loss of gene function. Unfortunately, this approach is laborious, and not all PTCs trigger NMD. More importantly, mounting evidence suggest that PTC mutations can also result in a transcriptional adaptation response that can mask the effects of a PTC-mediated gene knockout. In this chapter, we present a PTC-free gene knockout strategy that implements homology-directed DNA repair (HDR) with selectable markers to substantially reduce the complexity of the screening and validation of genome edits in cells containing more than one gene copy as in the case of the commonly used hypotriploid HEK293 cell line. We describe how to obtain a complete knockout of the Ligase IV protein (LIG4) and provide considerations for the application of this SelectRepair Knockout method to other genes.
(© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
(© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
