1. Cockayne syndrome group B protein regulates fork restart, fork progression and MRE11-dependent fork degradation in BRCA1/2-deficient cells.
- Author
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Batenburg NL, Mersaoui SY, Walker JR, Coulombe Y, Hammond-Martel I, Wurtele H, Masson JY, and Zhu XD
- Subjects
- BRCA1 Protein deficiency, BRCA1 Protein metabolism, BRCA2 Protein deficiency, BRCA2 Protein metabolism, Cell Line, Cell Line, Tumor, DNA chemistry, DNA metabolism, DNA Breaks, Double-Stranded, DNA Helicases metabolism, DNA Repair Enzymes metabolism, DNA Replication genetics, HCT116 Cells, HEK293 Cells, Humans, MRE11 Homologue Protein metabolism, Mutation, Poly-ADP-Ribose Binding Proteins metabolism, RNA Interference, BRCA1 Protein genetics, BRCA2 Protein genetics, DNA genetics, DNA Helicases genetics, DNA Repair, DNA Repair Enzymes genetics, MRE11 Homologue Protein genetics, Poly-ADP-Ribose Binding Proteins genetics
- Abstract
Cockayne syndrome group B (CSB) protein has been implicated in the repair of a variety of DNA lesions that induce replication stress. However, little is known about its role at stalled replication forks. Here, we report that CSB is recruited to stalled forks in a manner dependent upon its T1031 phosphorylation by CDK. While dispensable for MRE11 association with stalled forks in wild-type cells, CSB is required for further accumulation of MRE11 at stalled forks in BRCA1/2-deficient cells. CSB promotes MRE11-mediated fork degradation in BRCA1/2-deficient cells. CSB possesses an intrinsic ATP-dependent fork reversal activity in vitro, which is activated upon removal of its N-terminal region that is known to autoinhibit CSB's ATPase domain. CSB functions similarly to fork reversal factors SMARCAL1, ZRANB3 and HLTF to regulate slowdown in fork progression upon exposure to replication stress, indicative of a role of CSB in fork reversal in vivo. Furthermore, CSB not only acts epistatically with MRE11 to facilitate fork restart but also promotes RAD52-mediated break-induced replication repair of double-strand breaks arising from cleavage of stalled forks by MUS81 in BRCA1/2-deficient cells. Loss of CSB exacerbates chemosensitivity in BRCA1/2-deficient cells, underscoring an important role of CSB in the treatment of cancer lacking functional BRCA1/2., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
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