MORC2 regulates DNA damage response through a PARP1-dependent pathway.
MORC2 regulates DNA damage response through a PARP1-dependent pathway.
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MORC2 通过 PARP1 依赖性途径调节 DNA 损伤反应。
DOI：
10.1093/nar/gkz545
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发表时间：
2019
影响因子：
14.9
通讯作者：
Li Da Qiang
中科院分区：
文献类型：
--
作者：
Zhang Lin;Li Da Qiang
摘要小象科CW型锌指蛋白2（MORC 2）是一种新发现的染色质重塑酶，在DNA损伤反应（DDR）中具有重要作用，但其作用机制尚不清楚。在这里，我们表明，聚（ADP-核糖）聚合酶1（PARP 1），一个关键的染色质相关的酶负责在哺乳动物细胞中的聚（ADP-核糖）（PAR）聚合物的合成，相互作用和PARylates MORC 2在其保守的CW型锌指结构域内的两个残基。DNA损伤后，PARP 1将MORC 2募集到DNA损伤位点并催化MORC 2 PAR化，从而刺激其ATP酶和染色质重塑活性。MORC 2中PAR化残基的突变导致DNA损伤后细胞存活率降低。反过来，MORC 2通过增强乙酰转移酶NAT 10介导的PARP 1在赖氨酸949处的乙酰化来稳定PARP 1，这阻断了其在相同残基处的泛素化和随后由E3泛素连接酶CHFR降解。因此，MORC 2的耗竭或乙酰化缺陷型PARP 1突变体的表达损害DNA损伤诱导的PAR产生和PAR依赖性DNA修复蛋白对DNA损伤的募集，导致对遗传毒性应激的敏感性增强。总的来说，这些发现揭示了MORC 2和PARP 1在调节细胞对DNA损伤的反应中以前未被认识的机制联系。
Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.