title: BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork.
abstract: The tumor suppressor protein BRCA1 promotes homologous recombination (HR), a high-fidelity mechanism to repair DNA double-strand breaks (DSBs) that arise during normal replication and in response to DNA-damaging agents. Recent genetic experiments indicate that BRCA1 also performs an HR-independent function during the repair of DNA interstrand crosslinks (ICLs). Here we show that BRCA1 is required to unload the CMG helicase complex from chromatin after replication forks collide with an ICL. Eviction of the stalled helicase allows leading strands to be extended toward the ICL, followed by endonucleolytic processing of the crosslink, lesion bypass, and DSB repair. Our results identify BRCA1-dependent helicase unloading as a critical, early event in ICL repair.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Long
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Joukov
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Magda
authors.initials: M
authors.lastname: Budzowska
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: johannes_walter@hms.harvard.edu.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Walter
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D008957:Models, Genetic; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism / Q000502:physiology; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D019313:BRCA1 Protein; D002843:Chromatin; D004268:DNA-Binding Proteins; D025801:Ubiquitin; D029867:Xenopus Proteins; D004265:DNA Helicases