放疗和大部分化疗药物主要通过损伤染色体DNA引起肿瘤细胞的死亡，而在DNA损伤过程中，DNA损伤修复信号通路和细胞周期检查点被激活，可对DNA损伤进行修复，肿瘤细胞得以继续存活。细胞核MORC家族CW型锌指结构蛋白MORC2是一种可以致癌的染色质重塑酶，对DNA修复具有重要作用。目前，MORC2对于乳腺癌放化疗DNA损伤修复的具体机制尚不明确。
2020年2月29日，英国牛津大学出版社旗下《核酸研究》在线发表复旦大学附属肿瘤医院肿瘤研究所复旦大学生物医学研究院刘弘夷、刘莹莹、杨帆、张琳、张方淋、胡欣、邵志敏、李大强等学者的研究报告，探讨了MORC2对于乳腺癌放化疗DNA损伤修复的具体机制。
该研究发现，MORC2能够通过乙酰化，对DNA损伤时细胞周期检查点激活进行调控，进而影响DNA损伤修复。机制分析表明，MORC2第767位赖氨酸残基K767可被乙酰转移酶NAT10乙酰化，该过程未受干扰时可被脱乙酰酶SIRT2抵消。
放化疗引起DNA损伤时，NAT10从核仁移位至核质，显著增加MORC2的K767乙酰化，并且影响其与组蛋白H3第11位苏氨酸H3T11磷酸化结合，继而抑制细胞周期蛋白依赖激酶CDK1和细胞周期蛋白B1转录、激活细胞周期检查点，引起细胞周期减慢或停滞于DNA合成后期，以保证细胞有足够时间完成DNA合成、受损伤DNA的修复，避免未修复染色质的细胞进入有丝分裂期。
此外，该研究进一步证实，临床乳腺癌患者肿瘤标本NAT10表达与MORC2乙酰化水平成正比，利用英国剑桥大学发表于2014年《科学》的NAT10小分子靶向抑制剂重塑素，能够迫使细胞通过细胞周期DNA合成后期检查点，从而增强细胞对放化疗DNA损伤的敏感性。
重塑素（remodelin）
因此，该研究结果表明，NAT10靶向抑制剂联合放化疗有望为乳腺癌提供新的临床治疗策略，故有必要进一步开展临床前体内研究。
Nucleic Acids Res. 2020 Feb 29. [Epub ahead of print]
Acetylation of MORC2 by NAT10 regulates cell-cycle checkpoint control and resistance to DNA-damaging chemotherapy and radiotherapy in breast cancer.
Hong-Yi Liu, Ying-Ying Liu, Fan Yang, Lin Zhang, Fang-Lin Zhang, Xin Hu, Zhi-Min Shao, Da-Qiang Li.
Fudan University Shanghai Cancer Center and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai, China.
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.
DOI: 10.1093/nar/gkaa130
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