title: The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage.
abstract: In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate-dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21(Cip1) accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage.
authors.affiliation: Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
authors.forename: Dorthe Helena
authors.initials: DH
authors.lastname: Larsen
authors.forename: Catherine
authors.initials: C
authors.lastname: Poinsignon
authors.forename: Thorkell
authors.initials: T
authors.lastname: Gudjonsson
authors.forename: Christoffel
authors.initials: C
authors.lastname: Dinant
authors.forename: Mark R
authors.initials: MR
authors.lastname: Payne
authors.forename: Flurina J
authors.initials: FJ
authors.lastname: Hari
authors.forename: Jannie M
authors.initials: JM
authors.lastname: Rendtlew Danielsen
authors.forename: Patrice
authors.initials: P
authors.lastname: Menard
authors.forename: Jette Christensen
authors.initials: JC
authors.lastname: Sand
authors.forename: Manuel
authors.initials: M
authors.lastname: Stucki
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
mesh_terms: D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002875:Chromosomes / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair; D018816:Genes, cdc; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: D001324:Autoantigens; C115323:CHD4 protein, human; D002843:Chromatin; D034741:RNA, Small Interfering; D025801:Ubiquitin; D004247:DNA; D020687:cdc25 Phosphatases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
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