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ATM‐Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions
Advanced Science ( IF 15.1 ) Pub Date : 2020-09-03 , DOI: 10.1002/advs.202000157
Kaishun Hu 1 , Yu Li 1 , Wenjing Wu 1, 2 , Limin Xie 1 , Haiyan Yan 1 , Yuexin Cai 1 , Dong Chen 1 , Qiongchao Jiang 1, 3 , Lehang Lin 1 , Zhen Chen 1 , Jian‐You Liao 1 , Yin Zhang 1 , H. Phillip Koeffler 4 , Dong Yin 1 , Erwei Song 1, 2
Affiliation  

Repair of DNA double‐strand breaks (DSBs) is essential for genome integrity, and is accompanied by transcriptional repression at the DSB regions. However, the mechanisms how DNA repair induces transcriptional inhibition remain elusive. Here, it is identified that BRD7 participates in DNA damage response (DDR) and is recruited to the damaged chromatin via ATM signaling. Mechanistically, BRD7 joins the polycomb repressive complex 2 (PRC2), the nucleosome remodeling and histone deacetylation (NuRD) complex at the damaged DNA and recruits E3 ubiquitin ligase RNF168 to the DSBs. Furthermore, ATM‐mediated BRD7 phosphorylation is required for recruitment of the PRC2 complex, NuRD complex, DSB sensor complex MRE11‐RAD50‐NBS1 (MRN), and RNF168 to the active transcription sites at DSBs, resulting in transcriptional repression and DNA repair. Moreover, BRD7 deficiency sensitizes cancer cells to PARP inhibition. Collectively, BRD7 is crucial for DNA repair and DDR‐mediated transcription repression, which may serve as a therapeutic target. The findings identify the missing link between DNA repair and transcription regulation that maintains genome integrity.

中文翻译:

在侧翼转录活性区的DNA断裂处进行转录抑制和DNA修复需要BRD7的ATM依赖招募

DNA双链断裂(DSB)的修复对于基因组完整性至关重要,并伴随着DSB区的转录抑制。但是,DNA修复如何诱导转录抑制的机制仍然不清楚。在此,确定了BRD7参与DNA损伤应答(DDR),并通过ATM信号传导募集到受损的染色质上。从机制上讲,BRD7在受损的DNA处加入了多梳抑制复合物2(PRC2),核小体重塑和组蛋白去乙酰化(NuRD)复合物,并向DSB募集了E3泛素连接酶RNF168。此外,将PRC2复合物,NuRD复合物,DSB传感器复合物MRE11-RAD50-NBS1(MRN)和RNF168募集到DSB的活性转录位点需要ATM介导的BRD7磷酸化,从而导致转录抑制和DNA修复。此外,BRD7缺乏症会使癌细胞对PARP抑制敏感。总体而言,BRD7对于DNA修复和DDR介导的转录阻遏至关重要,这可以作为治疗靶标。这些发现确定了DNA修复与维持基因组完整性的转录调控之间的缺失联系。
更新日期:2020-10-22
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