MOF and H4 K16 Acetylation Play Important Roles in DNA Damage Repair by Modulating Recruitment of DNA Damage Repair Protein Mdc1
MOF and H4 K16 Acetylation Play Important Roles in DNA Damage Repair by Modulating Recruitment of DNA Damage Repair Protein Mdc1
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DOI：
10.1128/mcb.00350-10
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Dou, Yali
中科院分区：
文献类型：
--
作者：
Li, Xiangzhi;Corsa, Callie Ann Sprunger;Dou, Yali
MOF(MYST1)是催化组蛋白H4赖氨酸16(K16)乙酰化的主要酶，在进化过程中高度保守。利用条件性基因敲除小鼠模型和衍生的小鼠胚胎成纤维细胞系，我们发现MOF的缺失导致H4K16乙酰化水平降低，严重的G(2)/M细胞周期停滞，大量染色体畸变，以及电离辐射诱导的DNA损伤修复缺陷。我们进一步表明，尽管早期的DNA损伤感知和ATM信号在MOF缺失的细胞中是正常的，但修复中介蛋白MDc1及其下游信号蛋白53BP1和BRCA1对DNA损伤灶的募集完全被取消。机理研究表明，MOF介导了H4K16的乙酰化，并在H2A上形成了完整的酸性口袋。X对招募Mdc1是必不可少的。去除MOF及其相关蛋白的表型是一个H_2A的电荷中和突变体。鉴于H4-H2A在调节高阶染色质结构中的反式作用已被很好地描述，我们的研究揭示了一种新的基于染色质的机制来调节DNA损伤修复过程。
MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G(2)/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A. X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A. X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process.