Role of Chromatin Remodeling by RAD54 in DNA Damage Repair and Homologous Recombination

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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Regulation and pharmacological targeting of RAD51 in cancer

NAR Cancer ◽

10.1093/narcan/zcaa024 ◽

2020 ◽

Vol 2 (3) ◽

Author(s):

McKenzie K Grundy ◽

Ronald J Buckanovich ◽

Kara A Bernstein

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Patient Outcomes ◽

Cancer Biology ◽

Cancer Resistance ◽

Breast And Ovarian Cancer ◽

Resistance To Therapy ◽

Damage Repair

Abstract Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

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The role of the novel LincRNA uc002jit.1 in NF-kB-mediated DNA damage repair in acute myeloid leukemia cells

Experimental Cell Research ◽

10.1016/j.yexcr.2020.111985 ◽

2020 ◽

Vol 391 (2) ◽

pp. 111985 ◽

Cited By ~ 1

Author(s):

Ding Li ◽

Zelei Yu ◽

Tingting Wang ◽

Yi Li ◽

Xianling Chen ◽

...

Keyword(s):

Dna Damage ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Dna Damage Repair ◽

Leukemia Cells ◽

The Novel ◽

Damage Repair ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1

Nucleic Acids Research ◽

10.1093/nar/gkaa127 ◽

2020 ◽

Vol 48 (8) ◽

pp. 4480-4491 ◽

Cited By ~ 2

Author(s):

Xiaoyan Wang ◽

Xinyue Zhang ◽

Yujie Dang ◽

Duan Li ◽

Gang Lu ◽

...

Keyword(s):

Dna Damage ◽

Noncoding Rna ◽

Dna Damage Repair ◽

Noncoding Rnas ◽

Epigenetic Mechanism ◽

Premature Ovarian Insufficiency ◽

Genetic Etiology ◽

Ovarian Insufficiency ◽

Damage Repair

Abstract The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

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