title: Lysine 63-polyubiquitination guards against translesion synthesis-induced mutations.
abstract: Eukaryotic cells possess several mechanisms to protect the integrity of their DNA against damage. These include cell-cycle checkpoints, DNA-repair pathways, and also a distinct DNA damage-tolerance system that allows recovery of replication forks blocked at sites of DNA damage. In both humans and yeast, lesion bypass and restart of DNA synthesis can occur through an error-prone pathway activated following mono-ubiquitination of proliferating cell nuclear antigen (PCNA), a protein found at sites of replication, and recruitment of specialized translesion synthesis polymerases. In yeast, there is evidence for a second, error-free, pathway that requires modification of PCNA with non-proteolytic lysine 63-linked polyubiquitin (K63-polyUb) chains. Here we demonstrate that formation of K63-polyUb chains protects human cells against translesion synthesis-induced mutations by promoting recovery of blocked replication forks through an alternative error-free mechanism. Furthermore, we show that polyubiquitination of PCNA occurs in UV-irradiated human cells. Our findings indicate that K63-polyubiquitination guards against environmental carcinogenesis and contributes to genomic stability.
authors.affiliation: Department of Radiation Oncology, GROW Research Institute, University of Maastricht, Maastricht, Netherlands.
authors.forename: Roland K
authors.initials: RK
authors.lastname: Chiu
authors.forename: Jan
authors.initials: J
authors.lastname: Brun
authors.forename: Chantal
authors.initials: C
authors.lastname: Ramaekers
authors.forename: Jan
authors.initials: J
authors.lastname: Theys
authors.forename: Lin
authors.initials: L
authors.lastname: Weng
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gray
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
mesh_terms: D002273:Carcinogens; D045744:Cell Line, Tumor; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D008954:Models, Biological; D009154:Mutation; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D002273:Carcinogens; D025801:Ubiquitin; D008239:Lysine