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首页> 外文期刊>Molecular and Cellular Biology >Role of ATM and the Damage Response Mediator Proteins 53BP1 and MDC1 in the Maintenance of G2/M Checkpoint Arrest
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Role of ATM and the Damage Response Mediator Proteins 53BP1 and MDC1 in the Maintenance of G2/M Checkpoint Arrest

机译：ATM和损伤应答介体蛋白53BP1和MDC1在维持G2 / M检查站逮捕中的作用

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ATM-dependent initiation of the radiation-induced G2/M checkpoint arrest is well established. Recent results have shown that the majority of DNA double-strand breaks (DSBs) in G2 phase are repaired by DNA nonhomologous end joining (NHEJ), while ～15% of DSBs are slowly repaired by homologous recombination. Here, we evaluate how the G2/M checkpoint is maintained in irradiated G2 cells, in light of our current understanding of G2 phase DSB repair. We show that ATM-dependent resection at a subset of DSBs leads to ATR-dependent Chk1 activation. ATR-Seckel syndrome cells, which fail to efficiently activate Chk1, and small interfering RNA (siRNA) Chk1-treated cells show premature mitotic entry. Thus, Chk1 significantly contributes to maintaining checkpoint arrest. Second, sustained ATM signaling to Chk2 contributes, particularly when NHEJ is impaired by XLF deficiency. We also show that cells lacking the mediator proteins 53BP1 and MDC1 initially arrest following radiation doses greater than 3 Gy but are subsequently released prematurely. Thus, 53BP1?/? and MDC1?/? cells manifest a checkpoint defect at high doses. This failure to maintain arrest is due to diminished Chk1 activation and a decreased ability to sustain ATM-Chk2 signaling. The combined repair and checkpoint defects conferred by 53BP1 and MDC1 deficiency act synergistically to enhance chromosome breakage.
机译：辐射诱导的G 2 / M检查点停滞的ATM依赖性启动已被很好地确定。最近的结果表明，G 2 相中的大多数DNA双链断裂（DSB）通过DNA非同源末端连接（NHEJ）修复，而约15％的DSB通过同源重组缓慢修复。 。在这里，根据我们目前对G 2 阶段的了解，我们评估如何在照射的G 2 细胞中维持G 2 / M检查点DSB维修。我们显示在DSBs子集的ATM依赖切除导致ATR依赖Chk1激活。 ATR-Seckel综合征细胞无法有效激活Chk1，小的干扰RNA（siRNA）Chk1处理的细胞显示有丝分裂过早进入。因此，Chk1大大有助于维持检查站逮捕。其次，持续的ATM信号传递给Chk2尤其是在XLF缺乏导致NHEJ受损的情况下。我们还显示，缺乏介体蛋白53BP1和MDC1的细胞最初会在大于3 Gy的辐射剂量后停滞，但随后会过早释放。因此， 53BP1 ？/？和 MDC1 ？/？细胞在高剂量时表现出检查点缺陷。维持逮捕的失败是由于Chk1激活减少和维持ATM-Chk2信号传导的能力降低。 53BP1和MDC1缺乏症共同导致的修复和检查点缺陷合并发挥协同作用，以增强染色体断裂。

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