title: Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation.
abstract: Mutations of CSB account for the majority of Cockayne syndrome (CS), a devastating hereditary disorder characterized by physical impairment, neurological degeneration and segmental premature aging. Here we report the generation of a human CSB-knockout cell line. We find that CSB facilitates HR and represses NHEJ. Loss of CSB or a CS-associated CSB mutation abrogating its ATPase activity impairs the recruitment of BRCA1, RPA and Rad51 proteins to damaged chromatin but promotes the formation of 53BP1-Rif1 damage foci in S and G2 cells. Depletion of 53BP1 rescues the formation of BRCA1 damage foci in CSB-knockout cells. In addition, knockout of CSB impairs the ATM- and Chk2-mediated DNA damage responses, promoting a premature entry into mitosis. Furthermore, we show that CSB accumulates at sites of DNA double-strand breaks (DSBs) in a transcription-dependent manner. The kinetics of DSB-induced chromatin association of CSB is distinct from that of its UV-induced chromatin association. These results reveal novel, important functions of CSB in regulating the DNA DSB repair pathway choice as well as G2/M checkpoint activation.
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON, Canada.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Batenburg
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Thompson
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON, Canada zhuxu@mcmaster.ca.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Zhu
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D000075223:Poly-ADP-Ribose Binding Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
keywords: CSB; DNA damage checkpoint; DNA double‐strand break repair
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