Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress.
Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress.
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人类CST促进了全基因组RAD51募集到富含GC的重复序列，以响应复制应力。
DOI：
10.1016/j.celrep.2016.06.077
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发表时间：
2016-08-02
期刊：
影响因子：
8.8
通讯作者：
Chai W
中科院分区：
文献类型：
--
作者：
Chastain M;Zhou Q;Shiva O;Fadri-Moskwik M;Whitmore L;Jia P;Dai X;Huang C;Ye P;Chai W
端粒CTC1/STN1/TEN1 （CST）复合体最近被认为与基因组区域复制胁迫下促进复制恢复有关，但其确切作用尚不清楚。在这里，我们报道了STN1在全基因组富含gc的重复序列上富集，以响应羟基脲（HU）诱导的复制胁迫。STN1缺陷加剧了这些序列在复制胁迫下的脆弱性，导致染色体断裂。我们发现，在叉子失速时，CST蛋白形成与RAD51共定位的不同核灶。此外，复制应激诱导CST与RAD51以依赖atr的方式发生物理关联。引人注目的是，CST缺陷减少了hu诱导的RAD51焦点形成，减少了RAD51在端粒和非端粒富含gc的脆弱序列上的募集。总的来说，我们的研究结果表明，CST促进RAD51招募到富含gc的重复序列，以应对复制应激，从而促进复制重启，从而为基因组稳定性维持的机制提供了见解。Chastain等人发现，在复制胁迫下，端粒复合体CST与RAD51相互作用，并在富含gc的重复脆性位点富集。CST抑制抑制RAD51在脆弱位点的募集，导致基因组不稳定。
The telomeric CTC1/STN1/TEN1 (CST) complex has recently been implicated in promoting replication recovery under replications stress at genomic regions, yet its precise role is unclear. Here we report that STN1 is enriched at GC-rich repetitive sequences genome-wide in response to hydroxyurea (HU)-induced replication stress. STN1 deficiency exacerbates fragility of these sequences under replication stress, resulting in chromosome fragmentation. We find that upon fork stalling, CST proteins form distinct nuclear foci that colocalize with RAD51. Furthermore, replication stress induces physical association between CST with RAD51 in an ATR-dependent manner. Strikingly, CST deficiency diminishes HU-induced RAD51 foci formation and reduces RAD51 recruitment to telomeres and non-telomeric GC-rich fragile sequences. Collectively, our findings establish that CST promotes RAD51 recruitment to GC-rich repetitive sequences in response to replication stress to facilitate replication restart, thereby providing insights into the mechanism underlying genome stability maintenance. Chastain et al. find that under replication stress, telomeric complex CST interacts with RAD51 and is enriched at GC-rich repetitive fragile sites. CST suppression inhibits RAD51 recruitment to fragile sites, resulting in genome instability.