The Srs2 helicase dampens DNA damage checkpoint by recycling RPA from chromatin
The Srs2 helicase dampens DNA damage checkpoint by recycling RPA from chromatin
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DOI：
10.1073/pnas.2020185118
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发表时间：
2021-02-23
影响因子：
11.1
通讯作者：
Zhao, Xiaolan
中科院分区：
文献类型：
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作者：
Dhingra, Nalini;Kuppa, Sahiti;Zhao, Xiaolan
DNA损伤检查点诱导许多细胞变化以科普遗传毒性应激。然而，持续的检查点信号传导可能对生长有害，部分原因是细胞周期恢复的阻断。检查点阻尼对于对抗这种有害影响至关重要，但其机制仍有待了解。在这里，我们表明，DNA解旋酶Srs2删除一个关键的检查点传感器复合物，RPA，从染色质下调检查点信号在芽殖酵母。Srs2和RPA的拮抗作用得到了它们众多抑制性遗传相互作用的支持。重要的是，RPA与单链DNA（ssDNA）结合的适度减少挽救了由Srs2或其解旋酶活性丧失引起的超检查点信号传导。这种拯救与srs2突变体中染色质上积累的RPA和相关检查点激酶的减少相关。此外，我们的数据表明，Srs2调控RPA是分离的重组修复中的作用，关键是有助于遗传毒素抗性。我们的结论是，阻尼检查点Srs2介导的RPA从染色质回收艾滋病细胞生存的遗传毒性压力，并在其他类型的DNA交易的潜在影响。
The DNA damage checkpoint induces many cellular changes to cope with genotoxic stress. However, persistent checkpoint signaling can be detrimental to growth partly due to blockage of cell cycle resumption. Checkpoint dampening is essential to counter such harmful effects, but its mechanisms remain to be understood. Here, we show that the DNA helicase Srs2 removes a key checkpoint sensor complex, RPA, from chromatin to down-regulate checkpoint signaling in budding yeast. The Srs2 and RPA antagonism is supported by their numerous suppressive genetic interactions. Importantly, moderate reduction of RPA binding to single-strand DNA (ssDNA) rescues hypercheckpoint signaling caused by the loss of Srs2 or its helicase activity. This rescue correlates with a reduction in the accumulated RPA and the associated checkpoint kinase on chromatin in srs2 mutants. Moreover, our data suggest that Srs2 regulation of RPA is separable from its roles in recombinational repair and critically contributes to genotoxin resistance. We conclude that dampening checkpoint by Srs2-mediated RPA recycling from chromatin aids cellular survival of genotoxic stress and has potential implications in other types of DNA transactions.