ATM-Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions.
ATM-Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions.
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转录抑制和 DNA 修复需要 ATM 依赖的 BRD7 募集，以实现转录活性区域侧翼 DNA 断裂处的 DNA 修复
DOI：
10.1002/advs.202000157
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Song E
中科院分区：
文献类型：
--
作者：
Hu K;Li Y;Wu W;Xie L;Yan H;Cai Y;Chen D;Jiang Q;Lin L;Chen Z;Liao JY;Zhang Y;Koeffler HP;Yin D;Song E
DNA双链断裂（DSB）的修复对基因组完整性至关重要，并伴随着DSB区域的转录抑制。然而，DNA修复如何诱导转录抑制的机制仍然难以捉摸。在此，确定BRD 7参与DNA损伤反应（DDR），并通过ATM信号转导被募集到受损的染色质。在机制上，BRD 7在受损DNA处加入多梳阻遏复合物2（PRC 2）、核小体重塑和组蛋白脱乙酰化（NuRD）复合物，并将E3泛素连接酶RNF 168募集到DSB。此外，ATM介导的BRD 7磷酸化需要PRC 2复合物、NuRD复合物、DSB传感器复合物MRE 11-RAD 50-NBS 1（MRN）和RNF 168募集到DSB的活性转录位点，导致转录抑制和DNA修复。此外，BRD 7缺陷使癌细胞对PARP抑制敏感。总的来说，BRD 7对DNA修复和DDR介导的转录抑制至关重要，这可能是一个治疗靶点。这些发现确定了DNA修复和维持基因组完整性的转录调控之间缺失的环节。DNA双链断裂（DSB）的修复对基因组完整性至关重要，并伴随着DSB区域的转录抑制。ATM介导的BRD 7在Ser 263位点的磷酸化是将PRC 2复合物、NuRD复合物、DSB传感器复合物MRE 11-RAD 50-NBS 1（MRN）和RNF 168募集到DSB的活性转录位点所必需的，从而导致转录抑制和DNA修复。
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. Repair of DNA double‐strand breaks (DSBs) is essential for genome integrity, and is accompanied by transcriptional repression at the DSB regions. ATM‐mediated BRD7 phosphorylation at the Ser 263 site 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.
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