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1. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection 2015

   https://ncsu.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3db9MwELdYKyRegA0E3UZlJBDwEJo4H06kaajNWgajUK0dQnuJEsdWM6Dtmu6B_547x-3agnjg5SrnrpKtu7N_ts93hLwQUeRFrlKWk7HM8jKZW2EQKMvLYe3MsWyaEJuHOdWBW2nCKpdzop6o86nAM_KWE4QeXkn5_rvZtYVVo_B21ZTQ2CF1hgUcaqTeORu2z2-DPLbyMJsXerYbtqrEmY7HsNT52pq0PTOvLU3bYZNbd6d6Seo9IFfLwehIFKx_sB6S39JpEHXui2XKx_8f-ENy3wBX2q4sbZfckZM9clcHkIpyj-yaSaKkr00m6zePiOi3T9gnRk08fEmPxscnn9t0DmtgMT9qjY9puqAL-WP6U8K2n6aT3IhoHuzW0-8lzX7RYjIusgIjtKn_ikoQw1dT-knGY3LR647iU8tUdbAEQMeFpbxUui5PmYKdks2V46oszLmyRR55LBMsBxDLReAFTgbwX3JX2BljEXdAhAfcfUqox6TLZCqVHSlPARNAH8j5GXzzRWQ3wAiNQpNZlbUj0bftbpis6b1BDlDZCfoyaFSIWXGdIMIKXMfnf-UGPgBqDiiyQQ6X6kqM25fJra4a5PmKDQ6LtzDpRE5vKhnPBWQFvXxSGdSqj-AbANix_3zD1FYCmAx8kzMpxjopOGyzAbrBkF4ujXKtW38Off_f3T8g9wAZ-hgmwcJDUlvMb-QzUkMbbpIdfv4V6eg90m9c0w7QMHaapN7ufIx7-DuKB0P42unGTeOX0OoOu9A6jT_0LqF11nkLtM_6mn7RdICUVxT_P_AvfwPei0IL

   Boersma, Vera; Moatti, Nathalie; Segura-Bayona, Sandra; Peuscher, Marieke H....

   Nature (London), Vol. 521, Issue 7553, pp. 537 - 540.

   MAD2L2 regulates DNA repair at deprotected telomeres and at ionizing-radiation-induced double-stranded DNA breaks by inhibiting resection of the 5′ ends; the ends are thus shunted into the non-homo... Read more

   MAD2L2 regulates DNA repair at deprotected telomeres and at ionizing-radiation-induced double-stranded DNA breaks by inhibiting resection of the 5′ ends; the ends are thus shunted into the non-homologous end-joining pathway. MAD2L2/REV7 promotes genome integrity DNA polymerase ζ, composed of REV3, REV7 and an associated factor, REV1, mediates a type of DNA repair involving translesion synthesis, and hence its activity is highly mutagenic. Two studies exploring the DNA damage response have converged on REV7 (also known as MAD2L2) as a factor that, by itself, can promote maintenance of genome integrity. Several protective mechanisms that prevent telomere ends being recognized as a double-strand breaks (DSBs) and triggering an inappropriate DNA damage response were known. Jacqueline Jacobs and colleagues now show that REV7/MAD2L2 suppresses homology-dependent repair at deprotected telomeres and at irradiation-induced DSBs by inhibiting resection of the 5′ end. As a consequence, the ends are shunted into the non-homologous end-joining pathway. Sven Rottenberg and colleagues came to a similar conclusion by studying the development of resistance to PARP inhibitors. They found that REV7/MAD2L2 dictates pathway choice in BRCA-deficient cells and during immunoglobulin class switching. Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing 1 , 2 . Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3′ telomeric overhangs, indicating that MAD2L2 inhibits 5′ end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP 3 . Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5′ end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis 4 . Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5′ end resection downstream of RIF1. Read less

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2. Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer... 2017

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   Hengel, Sarah R.; Spies, M. Ashley; Spies, Maria

   Cell Chemical Biology, Vol. 24, Issue 9, pp. 1101 - 1119.

   To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity ... Read more

   To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase. Approval of drugs targeting poly-ADP-ribose polymerase is inspiring campaigns to identify new targets among DNA repair proteins and new inhibitors for personalized cancer treatments. This review discusses the state of the art in DNA repair inhibitors and how these small molecules are improving our understanding of the complex and interconnecting DNA repair processes. Read less

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3. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy... 2016

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   Fang, Evandro Fei; Kassahun, Henok; Croteau, Deborah L....

   Cell Metabolism, Vol. 24, Issue 4, pp. 566 - 581.

   Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator ... Read more

   Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions. [Display omitted] •Mitochondrial dysfunction and defective mitophagy shown in A-T animal models•A-T laboratory animal models exhibit NAD+ depletion and impaired SIRT1 activity•NAD+ replenishment improves lifespan and healthspan in ATM− worms and mice•NAD+ ameliorates A-T phenotypes through upregulation of mitophagy and DNA repair Mitochondrial damage and NAD+ depletion are key features in ataxia telangiectasia. Fang et al. show that mitochondrial dysfunction in ATM deficiency is caused by compromised mitophagy due to NAD+/SIRT1 inhibition. NAD+ replenishment significantly extends lifespan and improves healthspan in both ATM− worms and mice through mitophagy and DNA repair. Read less

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