Regulatory ubiquitylation in response to DNA double-strand breaks.
DNA double-strand breaks (DSBs) are highly cytolethal DNA lesions. In response to DSBs, cells initiate a complex response that minimizes their deleterious impact on cellular and organismal physiology. In this review, we discuss the discovery of a regulatory ubiquitylation system that modifies the chromatin that surrounds DNA lesions. This pathway is under the control of RNF8 and RNF168, two E3 ubiquitin ligases that cooperate with UBC13 to promote the relocalization of 53BP1 and BRCA1 to sites of DNA damage. RNF8 and RNF168 orchestrate the recruitment of DNA damage response proteins by catalyzing the ubiquitylation of H2A-type histones and the formation of K63-linked ubiquitin chains on damaged chromatin. Finally, we identify some unresolved issues raised by the discovery of this pathway and discuss the implications of DNA damage-induced ubiquitylation in human disease and development.
Panier
Stephanie
S
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Durocher
Daniel
D
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C486521:RNF8 protein, human; D004247:DNA; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases