Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.
Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.
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DOI：
10.1101/gad.252189.114
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发表时间：
2015-01-15
影响因子：
10.5
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Gong F;Chiu LY;Cox B;Aymard F;Clouaire T;Leung JW;Cammarata M;Perez M;Agarwal P;Brodbelt JS;Legube G;Miller KM
龚等人。报告称，超过三分之一的含溴结构域 (BRD) 的蛋白质会因 DNA 损伤而改变定位。他们将 ZMYND8 确定为一种新型 DNA 损伤反应因子，可招募核小体重塑和组蛋白脱乙酰化 (NuRD) 复合物来损伤染色质，从而抑制转录并通过同源重组促进修复。染色质如何塑造促进基因组-表观基因组完整性以应对 DNA 损伤的途径是一个至关重要的问题。我们报告说，含有人类溴结构域 (BRD) 的蛋白质是乙酰化染色质的主要“读者”，对于 DNA 损伤反应 (DDR) 至关重要。我们发现超过三分之一的人类 BRD 蛋白会因 DNA 损伤而改变定位。我们将 ZMYND8（锌指和 MYND [骨髓、Nervy 和 DEAF-1] 结构域包含 8）确定为一种新型 DDR 因子，可招募核小体重塑和组蛋白脱乙酰化 (NuRD) 复合物来修复受损的染色质。我们的数据定义了由 ZMYND8 和 NuRD 复合物介导的转录相关 DDR 通路，该通路针对 DNA 损伤，包括当它发生在转录活性染色质内时，以抑制转录并通过同源重组促进修复。因此，我们的数据将人类 BRD 蛋白确定为 DDR 的关键染色质调节剂，并提供了新的见解，了解活跃转录区域内的 DNA 损伤如何需要染色质结合蛋白来协调与损伤相关的染色质环境相一致的适当反应。
Gong et al. report that more than one-third of human bromodomain (BRD)-containing proteins change localization in response to DNA damage. They identified ZMYND8 as a novel DNA damage response factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin to repress transcription and promote repair by homologous recombination. How chromatin shapes pathways that promote genome–epigenome integrity in response to DNA damage is an issue of crucial importance. We report that human bromodomain (BRD)-containing proteins, the primary “readers” of acetylated chromatin, are vital for the DNA damage response (DDR). We discovered that more than one-third of all human BRD proteins change localization in response to DNA damage. We identified ZMYND8 (zinc finger and MYND [myeloid, Nervy, and DEAF-1] domain containing 8) as a novel DDR factor that recruits the nucleosome remodeling and histone deacetylation (NuRD) complex to damaged chromatin. Our data define a transcription-associated DDR pathway mediated by ZMYND8 and the NuRD complex that targets DNA damage, including when it occurs within transcriptionally active chromatin, to repress transcription and promote repair by homologous recombination. Thus, our data identify human BRD proteins as key chromatin modulators of the DDR and provide novel insights into how DNA damage within actively transcribed regions requires chromatin-binding proteins to orchestrate the appropriate response in concordance with the damage-associated chromatin context.
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