Jacob G. JansenPiya TemviriyanukulNiek WitFrédéric DelbosClaude Agnès ReynaudHeinz JacobsNiels D. WindLeiden University Medical Center - LUMCThe Netherlands Cancer InstituteCNRS Centre National de la Recherche ScientifiqueMahidol UniversityThe Medical Research Council Laboratory of Molecular BiologyInserm2018-11-092018-11-092014-06-27Nucleic Acids Research. Vol.42, No.17 (2014), 11071-1108213624962030510482-s2.0-84922513826https://repository.li.mahidol.ac.th/handle/20.500.14594/33249© The Author(s) 2014. Short-wave ultraviolet light induces both mildly helixdistorting cyclobutane pyrimidine dimers (CPDs) and severely distorting (6-4) pyrimidine pyrimidone photoproducts ((6-4)PPs). The only DNA polymerase (Pol) that is known to replicate efficiently across CPDs is Polη, a member of the Y family of translesion synthesis (TLS) DNA polymerases. Phenotypes of Polη deficiency are transient, suggesting redundancy with other DNA damage tolerance pathways. Here we performed a comprehensive analysis of the temporal requirements of Y-family Pols ι and κ as backups for Polη in (i) bypassing genomic CPD and (6-4)PP lesions in vivo, (ii) suppressing DNA damage signaling, (iii) maintaining cell cycle progression and (iv) promoting cell survival, by using mouse embryonic fibroblast lines with single and combined disruptions in these Pols. The contribution of Poι is restricted to TLS at a subset of the photolesions. Polκ plays a dominant role in rescuing stalled replication forks in Polη-deficient mouse embryonic fibroblasts, both at CPDs and (6-4)PPs. This dampens DNA damage signaling and cell cycle arrest, and results in increased survival. The role of relatively error-prone Pols ι and κ as backups for Polη contributes to the understanding of the mutator phenotype of xeroderma pigmentosum variant, a syndrome caused by Polη defects.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1093/nar/gku779