SIRT6 Promotes DNA Repair Under Stress by Activating PARP1

Mao, Zhiyong; Hine, Christopher; Tian, Xiao; Meter, Michael Van; Au, Matthew; Vaidya, Amita; Seluanov, Andrei; Gorbunova, Vera

doi:10.1126/science.1202723

Cited by 759 publications

(793 citation statements)

References 35 publications

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“…Accordingly, 53BP1 deletion in BRCA1‐deficient cells allows replication protein A (RPA) loading and restoration of HR. A previous report suggested that SIRT7 may regulate HR repair (Mao et al , 2011). However, the absence of SIRT7 did not lead to a detectable change of HR levels, as measured by RAD51 focus formation (Appendix Fig S5A–C), by measuring SCE events, or by using a HR reporter locus (Appendix Fig S7C–G).…”

Section: Discussionmentioning

confidence: 99%

“…It will be interesting to investigate whether PARP activity affects SIRT7‐mediated transcriptional regulation such as the regulation of ribosomal gene expression. On the other hand, SIRT6‐mediated mono‐ADP ribosylation of PARP1 enhances its activity as a DNA repair mediator (Mao et al , 2011). Our results suggests that PARP proteins, at least at the level of DNA repair, are acting upstream of SIRT7 (Fig 6F and G).…”

Section: Discussionmentioning

confidence: 99%

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SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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“…Similarly, pretreatment with heat shock resulted in improved DNA repair in yeast [50]. More generally, sirtuin protein (SIRT6) has recently been shown to stimulate DNA repair in cells under increased oxidative stress [51]. This multifunctional protein is a member of sirtuin family of proteins that play a key role in regulating metabolism, lifespan (but see Burnett et al [52]), chromosomal stability and stress response across taxa [53,54].…”

Section: Discussionmentioning

confidence: 99%

The effect of sexual harassment on lethal mutation rate in femaleDrosophila melanogaster

et al. 2013

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The rate by which new mutations are introduced into a population may have far-reaching implications for processes at the population level. Theory assumes that all individuals within a population have the same mutation rate, but this assumption may not be true. Compared with individuals in high condition, those in poor condition may have fewer resources available to invest in DNA repair, resulting in elevated mutation rates. Alternatively, environmentally induced stress can result in increased investment in DNA repair at the expense of reproduction. Here, we directly test whether sexual harassment by males, known to reduce female condition, affects female capacity to alleviate DNA damage in Drosophila melanogaster fruitflies. Female gametes can repair double-strand DNA breaks in sperm, which allows manipulating mutation rate independently from female condition. We show that male harassment strongly not only reduces female fecundity, but also reduces the yield of dominant lethal mutations, supporting the hypothesis that stressed organisms invest relatively more in repair mechanisms. We discuss our results in the light of previous research and suggest that social effects such as density and courtship can play an important and underappreciated role in mediating condition-dependent mutation rate.

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“…Among the gene targeting models for seven mammalian sirtuins, SIRT6-deficient mice displayed a prominent premature aging phenotype accompanied by shortened life span (12,13). SIRT6 has been demonstrated to regulate longevity by a variety of mechanisms, including NF-kB inhibition, base excision repair, homologous recombination, and modulation of insulin-like growth factor (IGF)-I signaling (13)(14)(15)(16)(17)(18). Although IGF-I signaling has been reported to be involved in autophagy and cellular senescence (19), autophagy modulation by SIRT6 and implication of SIRT6 in regulation of cellular senescence during COPD pathogenesis remain to be elucidated.…”

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confidence: 99%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

165

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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SIRT6 Promotes DNA Repair Under Stress by Activating PARP1

Cited by 759 publications

References 35 publications

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

The effect of sexual harassment on lethal mutation rate in femaleDrosophila melanogaster

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

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