SIRT7: a sentinel of genome stability

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

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AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

10.21203/rs.3.rs-378687/v1 ◽

2021 ◽

Author(s):

Bing Sun ◽

McLean Sherrin ◽

Richard Roy

Keyword(s):

Dna Damage ◽

Genome Stability ◽

Germ Line ◽

Critical Role ◽

Significant Proportion ◽

Loop Formation ◽

C Elegans ◽

Chromatin Activation ◽

Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

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SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

Science Advances ◽

10.1126/sciadv.aav1118 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaav1118 ◽

Cited By ~ 19

Author(s):

Ming Tang ◽

Zhiming Li ◽

Chaohua Zhang ◽

Xiaopeng Lu ◽

Bo Tu ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Class Iii ◽

Ataxia Telangiectasia Mutated ◽

Damage Repair ◽

Damage Response ◽

Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

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Multifunctional Role of ATM/Tel1 Kinase in Genome Stability: From the DNA Damage Response to Telomere Maintenance

BioMed Research International ◽

10.1155/2014/787404 ◽

2014 ◽

Vol 2014 ◽

pp. 1-17 ◽

Cited By ~ 16

Author(s):

Enea Gino Di Domenico ◽

Elena Romano ◽

Paola Del Porto ◽

Fiorentina Ascenzioni

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Ataxia Telangiectasia ◽

Genome Stability ◽

Genetic Disorder ◽

Cell Cycle Control ◽

Premature Aging ◽

Telomere Maintenance ◽

Damage Response

The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere maintenance and length regulation. Likewise, inSaccharomyces cerevisiae, haploid strains defective in theTEL1gene, the ATM ortholog, show chromosomal aberrations and short telomeres. In this review, we outline the complex role of ATM/Tel1 in maintaining genomic stability through its control of numerous aspects of cellular survival. In particular, we describe how ATM/Tel1 participates in the signal transduction pathways elicited by DNA damage and in telomere homeostasis and its importance as a barrier to cancer development.

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The Roles of SPOP in DNA Damage Response and DNA Replication

International Journal of Molecular Sciences ◽

10.3390/ijms21197293 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7293

Author(s):

Masashi Maekawa ◽

Shigeki Higashiyama

Keyword(s):

Dna Damage ◽

Dna Replication ◽

Dna Damage Response ◽

Genome Stability ◽

Substrate Binding ◽

Critical Role ◽

Tumor Formation ◽

Missense Mutations ◽

Cellular Functions ◽

Damage Response

Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of these SPOP mutants, thus, causes aberrant turnovers of the substrate proteins, leading to tumor formation. Although the molecular properties of SPOP and its cancer-associated mutants have been intensively elucidated, their cellular functions remain unclear. Recently, a number of studies have uncovered the critical role of SPOP and its mutants in DNA damage response and DNA replication. In this review article, we summarize the physiological functions of SPOP as a “gatekeeper” of genome stability.

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Role of Deubiquitinating Enzymes in DNA Repair

Molecular and Cellular Biology ◽

10.1128/mcb.00847-15 ◽

2015 ◽

Vol 36 (4) ◽

pp. 524-544 ◽

Cited By ~ 34

Author(s):

Younghoon Kee ◽

Tony T Huang

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Mammalian Cells ◽

Genome Stability ◽

Regulatory Mechanisms ◽

Deubiquitinating Enzymes ◽

Genome Maintenance ◽

Dna Damage Signaling ◽

Damage Response

Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling.

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Critical Role of Monoubiquitination of Histone H2AX Protein in Histone H2AX Phosphorylation and DNA Damage Response

Journal of Biological Chemistry ◽

10.1074/jbc.m111.257469 ◽

2011 ◽

Vol 286 (35) ◽

pp. 30806-30815 ◽

Cited By ~ 54

Author(s):

Ching-Yuan Wu ◽

Hong-Yo Kang ◽

Wei-Lei Yang ◽

Juan Wu ◽

Yun Seong Jeong ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Critical Role ◽

H2ax Phosphorylation ◽

Histone H2ax ◽

Damage Response ◽

Histone H2ax Phosphorylation

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Succinylation at a key residue of FEN1 is involved in the DNA damage response to maintain genome stability

AJP Cell Physiology ◽

10.1152/ajpcell.00137.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. C657-C666

Author(s):

Rongyi Shi ◽

Yiyi Wang ◽

Ya Gao ◽

Xiaoli Xu ◽

Shuyu Mao ◽

...

Keyword(s):

Dna Damage ◽

Dna Replication ◽

Replication Fork ◽

Genome Stability ◽

Damage Response ◽

Dna Replication And Repair ◽

Fork Stalling ◽

Stalled Replication Forks ◽

Maintain Genome Stability

Human flap endonuclease 1 (FEN1) is a structure-specific, multifunctional endonuclease essential for DNA replication and repair. Our previous study showed that in response to DNA damage, FEN1 interacts with the PCNA-like Rad9-Rad1-Hus1 complex instead of PCNA to engage in DNA repair activities, such as stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as ultraviolet (UV) irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintaining genome stability.

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