SIRT2 orchestrates the DNA damage response.
SIRT2 orchestrates the DNA damage response.
复制标题
SIRT2 协调 DNA 损伤反应。
DOI：
10.1080/15384101.2016.1184517
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Yu,DavidS
中科院分区：
文献类型：
--
作者：
Zhang,Hui;Head,PamelaSaraE;Yu,DavidS
Sirtuin 2 (SIRT2), is a member of the sirtuin family of NAD+ dependent deacetylases, which are implicated in diverse biological processes, including metabolism, aging, genome maintenance, and tumor suppression. SIRT2 is critical for tumor suppression and genome maintenance. Sirt2 knockout mice develop breast, liver, and other cancers, and SIRT2 expression is reduced in human breast and liver cancers. 1 These cancers also express genome instability, suggesting that SIRT2’s role in tumor suppression may at least in part be due to its functions in protecting against DNA damage. The DNA damage response (DDR) is a signaling network, which recognizes DNA lesions and mobilizes cellular events to maintain genome integrity. Thus, the DDR is a critical barrier against genomic instability and carcinogenesis. Recent studies have demonstrated SIRT2’s crucial function in the DDR through protein deacetylation. SIRT2 regulates anaphase promoting complex/cyclosome (APC/C) activity during mitosis by deacetylating APC/C coactivators CDH1 and CDC20. 1 SIRT2 also deacetylates histone H3 on lysine 56, a signature chromatin mark for packaging DNA into chromatin upon DNA replication and repair. 2 Likewise, we have found that SIRT2 deacetylates CDK9 on lysine 48, thereby promoting recovery from replication stress. 3 Most recently, we found that SIRT2 deacetylates ATRIP at lysine 32, which drives ATR activation by facilitating binding to RPA-coated single stranded-DNA in response to replication stress. 4 The regulation of CDK9 and ATRIP-ATR by SIRT2 deacetylation is unlikely redundant since ATR depletion impairs hydroxyurea (HU) regulated deacetylation of CDK9, suggesting that ATR regulation is epistatic to that of CDK9. 3 Overall, our study revealed that SIRT2 deacetylase activity is essential for the ATR checkpoint pathway and helps explain how loss of Sirt2 results in compromised genomic stability and tumorigenesis. Our findings also suggest that SIRT2 is capable of deacetylating multiple key components within the ATR signaling pathway, perhaps to amplify or fine-tune the signal. Our studies, together with others, implicate SIRT2 in controlling various aspects and levels of the DDR, suggesting that SIRT2 functions as a master regulator of the DDR. To fully characterize the comprehensive landscape of the SIRT2 acetylome in the DDR is thus of great interest for elucidating the mechanism by which SIRT2 promotes genome integrity and prevents cancer.
