Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress

• DOI: 10.1016/j.celrep.2016.06.077
• Publication Date: 2016-08-02T18:16:20Z
• Authors: Megan Chastain; Qing Zhou; Olga Shiva; Maria Fadri-Moskwik; Leanne Whitmore; Pingping Jia; Xueyu Dai; Chenhui Huang; Ping Ye; Weihang Chai
• Keywords: DNA Replication; 0301 basic medicine; 0303 health sciences; Genome; QH301-705.5; replication stress; Chromosome Fragility; Telomere-Binding Proteins; CTC1/STN1/TEN1; Telomere Homeostasis; DNA Fragmentation; Telomere; Genomic Instability; GC Rich Sequence; 03 medical and health sciences; Cell Line, Tumor; RAD51; Humans; Rad51 Recombinase; Biology (General); genome stability; HeLa Cells; Repetitive Sequences, Nucleic Acid

The telomeric CTC1/STN1/TEN1 (CST) complex has been implicated in promoting replication recovery under replication 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 the 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 of 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.