KEOPS complex promotes homologous recombination via DNA resection
KEOPS complex promotes homologous recombination via DNA resection
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DOI：
10.1093/nar/gkz228
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发表时间：
2019-06-20
影响因子：
14.9
通讯作者：
Zhou, Jin-Qiu
中科院分区：
文献类型：
--
作者：
He, Ming-Hong;Liu, Jia-Cheng;Zhou, Jin-Qiu
KEOPS复合物是真核生物中最保守的蛋白质复合物之一。它在芽殖酵母端粒脱帽和tRNA N-6-苏氨酰氨基甲酰基腺苷（t（6）A）修饰中起重要作用。但KEOPS复合物是否在DNA修复中发挥作用仍不清楚。在此，我们发现KEOPS复合物在DNA损伤反应和同源重组介导的DNA修复中起着积极的作用，而与其t（6）A合成功能无关。此外，KEOPS在体外显示出DNA结合活性，并在体内DNA断裂时被募集到染色质中，表明KEOPS在DSB修复中的直接作用。从机制上讲，KEOPS复合物似乎通过促进Exo 1和Dna 2与DNA断裂的结合来促进DNA末端切除。有趣的是，KEOPS和Mre 11/Rad 50/Xrs 2（MRX）复合物的失活导致DNA切割的协同缺陷，揭示了KEOPS和MRX在DNA切割中具有一些冗余功能。因此，我们揭示了一个t（6）A-独立的作用，KEOPS复合物在DNA切除，并提出KEOPS可能是一个DSB传感器，以帮助细胞维持染色体的稳定性。
KEOPS complex is one of the most conserved protein complexes in eukaryotes. It plays important roles in both telomere uncapping and tRNA N-6-threonylcarbamoyladenosine (t(6)A) modification in budding yeast. But whether KEOPS complex plays any roles in DNA repair remains unknown. Here, we show that KEOPS complex plays positive roles in both DNA damage response and homologous recombination-mediated DNA repair independently of its t(6)A synthesis function. Additionally, KEOPS displays DNA binding activity in vitro, and is recruited to the chromatin at DNA breaks in vivo, suggesting a direct role of KEOPS in DSB repair. Mechanistically, KEOPS complex appears to promote DNA end resection through facilitating the association of Exo1 and Dna2 with DNA breaks. Interestingly, inactivation of both KEOPS and Mre11/Rad50/Xrs2 (MRX) complexes results in synergistic defect in DNA resection, revealing that KEOPS and MRX have some redundant functions in DNA resection. Thus we uncover a t(6)A-independent role of KEOPS complex in DNA resection, and propose that KEOPS might be a DSB sensor to assist cells in maintaining chromosome stability.