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

Abstract

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.

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

“…Furthermore, hyperacetylated p53 accumulates in cells lacking SIRT7, resulting in apoptosis (78). SIRT7 also serves to protect against cell death from persistent DDR by deacetylating ATM late in the DSBR process with failed deacetylation of ATM promoting retention of gH2AX and apoptosis or senescence (23). Based on the results reported here, as well as previously published studies, we propose that activation of the KP in gliomas facilitates SIRT7-mediated recruitment of 53BP1 and subsequent repair of DSBs (Fig.…”

“…We were intrigued by the identification of SIRT7 specifically because of its multifaceted role in regulating chromatin condensation, DNA repair dynamics, tolerance of endoplasmic reticulum (ER) stress, and mitochondrial homeostasis (21)(22)(23)(24)(25)(26). One function of SIRT7 is to promote tolerance of ER stress by suppressing Myc activity and silencing expression of ribosomal proteins (22).…”

“…Others have shown that SIRT7 activity promotes 53BP1 recruitment through deacetylation of histone H3K18 (61). One study reported that SIRT7-catalyzed deacetylation was required to dissociate ATM from chromatin and completion of DSBR (23). Failure to deacetylate ATM led to increased levels of chromatinbound 53BP1 and RPA2 (23).…”

“…One study reported that SIRT7-catalyzed deacetylation was required to dissociate ATM from chromatin and completion of DSBR (23). Failure to deacetylate ATM led to increased levels of chromatinbound 53BP1 and RPA2 (23). Given that SIRT7 was identified in our proteomics analysis as being altered by modulation of the KP, we decided to investigate whether the impaired recruitment of 53BP1 could be related to changes in SIRT7 action (Fig.…”

The current progress of histone deacetylase SIRT7

“…H3K36的去乙酰化有助于rDNA(ribosomal DNA)异染 色质沉默和基因组稳定性、转录延伸或DNA损伤修 复 [9,10] . 此外, SIRT7的非组蛋白去乙酰化底物包括 p53 [11] , PAF53 [12] , U3-55k [13] , GABPβ1 [14] , NPM1 [15] , PGK1 [16] , CDK9 [17] , DDB1 [18,19] , FKBP51 [20] , FOXO3 [21] , SMAD4 [22] , DDX21 [23] , WDR77 [24] , Fibrillarin [25] , ATM [26] 和Ran [27] 等.…”