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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage
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ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage

机译：ATR-Chk1激活可缓解由于不匹配修复所依赖的DNA损伤加工而引起的复制压力

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The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA replication forks is unclear. This has important implications for understanding how MMR repairs O6-methylguanine/thymidine (MeG/T) mismatches created upon exposure to DNA alkylating agents. If MeG/T lesion recognition by MMR initiates mismatch excision, the reinsertion of a mismatched thymidine during resynthesis could initiate futile repair cycles. One consequence of futile repair cycles might be a disruption of overall DNA replication in the affected cell. Herein, we show that in MMR-proficient HeLa cancer cells, treatment with a DNA alkylating agent slows S phase progression, yet cells still progress into the next cell cycle. In the first S phase following treatment, they activate ataxia telangiectasia and Rad3-related (ATR)-Checkpoint Kinase 1 (Chk1) signaling, which limits DNA damage, while inhibition of ATR kinase activity accelerates DNA damage accumulation and sensitivity to the DNA alkylating agent. We also observed that exposure of human embryonic stem cells to alkylation damage severely compromised DNA replication in a MMR-dependent manner. These cells fail to activate the ATR-Chk1 signaling axis, which may limit their ability to handle replication stress. Accordingly, they accumulate double-strand breaks and undergo immediate apoptosis. Our findings implicate the MMR-directed response to alkylation damage as a replication stress inducer, suggesting that repeated MMR processing of mismatches may occur that can disrupt S phase progression.
机译：错配修复途径（MMR）对于消除DNA聚合酶错误，从而维持基因组稳定性至关重要。 MMR功能丧失会增加突变频率，并与肿瘤发生有关。但是，不清楚如何在主动DNA复制叉处执行MMR。这对于理解MMR如何修复因暴露于DNA烷基化剂而产生的O 6 -甲基鸟嘌呤/胸苷（ Me G / T）错配具有重要意义。如果MMR对 Me G / T病变的识别启动了错配切除，则在重新合成过程中重新插入错配的胸苷可能会导致无效的修复周期。徒劳的修复周期的结果之一可能是破坏了受影响细胞中的整体DNA复制。本文中，我们显示了在MMR精通的HeLa癌细胞中，用DNA烷基化剂处理会减慢S期进程，但细胞仍会进入下一细胞周期。在治疗后的第一个S期中，它们激活共济失调毛细血管扩张和Rad3相关（ATR）-Checkpoint激酶1（Chk1）信号传导，从而限制DNA损伤，同时抑制ATR激酶活性会加速DNA损伤的积累和对DNA烷基化剂的敏感性。 。我们还观察到，人类胚胎干细胞暴露于烷基化损害以MMR依赖性方式严重损害了DNA复制。这些细胞无法激活ATR-Chk1信号转导轴，这可能会限制它们处理复制压力的能力。因此，它们积累双链断裂并立即发生凋亡。我们的发现暗示了针对烷基化损伤的MMR定向反应是复制应激诱导物，表明重复发生的错配重复MMR处理可能会破坏S期进程。

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