Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Nucleic Acids Res. 2020 Apr 17;48(7):3638-3656. doi: 10.1093/nar/gkaa130.
MORC family CW-type zinc finger 2 (MORC2) is an oncogenic chromatin-remodeling enzyme with an emerging role in DNA repair. Here, we report a novel function for MORC2 in cell-cycle checkpoint control through an acetylation-dependent mechanism. MORC2 is acetylated by the acetyltransferase NAT10 at lysine 767 (K767Ac) and this process is counteracted by the deacetylase SIRT2 under unperturbed conditions. DNA-damaging chemotherapeutic agents and ionizing radiation stimulate MORC2 K767Ac through enhancing the interaction between MORC2 and NAT10. Notably, acetylated MORC2 binds to histone H3 phosphorylation at threonine 11 (H3T11P) and is essential for DNA damage-induced reduction of H3T11P and transcriptional repression of its downstream target genes CDK1 and Cyclin B1, thus contributing to DNA damage-induced G2 checkpoint activation. Chemical inhibition or depletion of NAT10 or expression of an acetylation-defective MORC2 (K767R) forces cells to pass through G2 checkpoint, resulting in hypersensitivity to DNA-damaging agents. Moreover, MORC2 acetylation levels are associated with elevated NAT10 expression in clinical breast tumor samples. Together, these findings uncover a previously unrecognized role for MORC2 in regulating DNA damage-induced G2 checkpoint through NAT10-mediated acetylation and provide a potential therapeutic strategy to sensitize breast cancer cells to DNA-damaging chemotherapy and radiotherapy by targeting NAT10.
MORC 家族 CW 型锌指 2（MORC2）是一种致癌性染色质重塑酶，在 DNA 修复中具有新兴作用。在这里，我们通过依赖于乙酰化的机制报告了 MORC2 在细胞周期检查点控制中的新功能。MORC2 在赖氨酸 767（K767Ac）处被乙酰转移酶 NAT10 乙酰化，并且在未受干扰的条件下，该过程被去乙酰化酶 SIRT2 抵消。DNA 损伤化学治疗药物和电离辐射通过增强 MORC2 和 NAT10 之间的相互作用来刺激 MORC2 K767Ac。值得注意的是，乙酰化的 MORC2 与组蛋白 H3 第 11 位苏氨酸（H3T11P）的磷酸化结合，并且对于 DNA 损伤诱导的 H3T11P 减少和其下游靶基因 CDK1 和 Cyclin B1 的转录抑制是必需的，从而有助于 DNA 损伤诱导的 G2 检查点激活。NAT10 的化学抑制或耗尽或表达乙酰化缺陷型 MORC2（K767R）迫使细胞通过 G2 检查点，导致对 DNA 损伤剂的敏感性增加。此外，MORC2 乙酰化水平与临床乳腺癌样本中 NAT10 表达的升高相关。总之，这些发现揭示了 MORC2 通过 NAT10 介导的乙酰化在调节 DNA 损伤诱导的 G2 检查点中的先前未被认识的作用，并提供了一种通过靶向 NAT10 使乳腺癌细胞对 DNA 损伤性化学疗法和放射疗法敏感的潜在治疗策略。
