PT  - JOURNAL ARTICLE
AU  - Xinxing Lyu
AU  - Kai-Hang Lei
AU  - Olga Shiva
AU  - Megan Chastain
AU  - Peter Chi
AU  - Weihang Chai
TI  - Human CST complex protects replication fork stability by directly blocking MRE11 degradation of nascent strand DNA
AID  - 10.1101/797647
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 797647
4099  - http://biorxiv.org/content/early/2019/10/08/797647.short
4100  - http://biorxiv.org/content/early/2019/10/08/797647.full
AB  - Degradation and collapse of stalled replication forks are main sources of genome instability, yet the molecular mechanism for protecting forks from degradation/collapse is not well understood. Here, we report that human CST (CTC1-STN1-TEN1), a single-stranded DNA binding protein complex, localizes at stalled forks and protects forks from MRE11 nuclease degradation upon replication perturbation. CST deficiency causes nascent strand degradation, ssDNA accumulation after fork stalling, and delay in replication recovery, leading to cellular sensitivity to fork stalling agents. Purified CST binds to 5’ overhangs and directly blocks MRE11 degradation in vitro, and the DNA binding ability of CST is required for blocking MRE11-mediated nascent strand degradation. Finally, we uncover that CST and BRCA2 form non-overlapping foci upon fork stalling, and CST inactivation is synthetic with BRCA2 deficiency in inducing genome instability. Collectively, our findings identify CST as an important fork protector to preserve genome integrity under replication perturbation.