1270–1280 Nucleic Acids Research, 2017, Vol. 45, No. 3 Published online 3 December 2016 doi: 10.1093/nar/gkw1196 Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells Leticia K. Lerner1,†, Guilherme Francisco2, Daniela T. Soltys3, Clarissa R.R. Rocha1, Annabel Quinet1, Alexandre T. Vessoni1, Ligia P. Castro1, Taynah I.P. David4, Silvina O. Bustos2, Bryan E. Strauss4, Vanesa Gottifredi5, Anne Stary6, Alain Sarasin6, Roger Chammas2 and Carlos F.M. Menck1,*
1Department of Microbiology, Institute of Biomedical Sciences, University of Sao˜ Paulo, Sao˜ Paulo, 05508-000, Brazil, 2Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of Sao˜ Paulo-ICESP, Sao˜ Paulo, 01246-000, Brazil, 3Department of Biochemistry, Institute of Chemistry, University of Sao˜ Paulo, Sao˜ Paulo, 05508-000, Brazil, 4Viral Vector Laboratory, Heart Institute, University of Sao˜ Paulo, Sao˜ Paulo, 05403-900, Brazil, 5Cell Cycle and Genomic Stability Laboratory, Fundacion´ Instituto Leloir-CONICET, Buenos Aires, C1405BWE, Argentina and 6CNRS-UMR8200, Universite´ Paris-Sud, Institut de Cancerologie´ Gustave Roussy, 94805 Villejuif, France
Received September 25, 2015; Revised November 15, 2016; Editorial Decision November 16, 2016; Accepted November 17, 2016
ABSTRACT INTRODUCTION Genome lesions trigger biological responses that Ultraviolet light (UV) damages DNA primarily through help cells manage damaged DNA, improving cell sur- the formation of two bulky lesions, cyclobutane pyrimidine vival. Pol eta is a translesion synthesis (TLS) poly- dimers (CPDs) and (6-4)-photoproducts (6-4PPs), which merase that bypasses lesions that block replicative distort the DNA structure and cause the stalling of replica- polymerases, avoiding continued stalling of replica- tive polymerases. Cells have evolved different mechanisms to avoid the deleterious effects of DNA damage, includ- tion forks, which could lead to cell death. p53 also ing their removal by nucleotide excision repair (NER) (1). plays an important role in preventing cell death after For unrepaired lesions, the replication of damaged DNA ultraviolet (UV) light exposure. Intriguingly, we show uses specialized translesion synthesis (TLS) polymerases that p53 does so by favoring translesion DNA synthe- that can bypass these lesions (2). In humans, a failure of sis by pol eta. In fact, the p53-dependent induction of these mechanisms leads to genetic syndromes, such as xero- pol eta in normal and DNA repair-deficient XP-C hu- derma pigmentosum (XP) and Cockayne syndrome (CS), man cells after UV exposure has a protective effect on which possess complex phenotypes of a high frequency of cell survival after challenging UV exposures, which cancer and/or severe neurodegeneration and aging (1,2). was absent in p53- and Pol H-silenced cells. Viability TLS is a conserved mechanism triggered by DNA poly- increase was associated with improved elongation merases, which have active sites capable of accommodating of nascent DNA, indicating the protective effect was damaged templates. Thus, this mechanism of DNA dam- age tolerance helps the replisome when it encounters un- due to more efficient lesion bypass by pol eta. This repaired lesions (3). However, the same structural adapta- protection was observed in cells proficient or defi- tions that allow these polymerases to bypass lesions lead cient in nucleotide excision repair, suggesting that, to a very low fidelity when copying undamaged DNA tem- from a cell survival perspective, proper bypass of plates, which may ultimately increase the risk of mutagene- DNA damage can be as relevant as removal. These sis (3). The main TLS polymerases belong to the Y-family, results indicate p53 controls the induction of pol eta such as the eukaryotic pols eta, iota, kappa and REV1, and in DNA damaged human cells, resulting in improved to the B-family, including pol zeta, which is formed by the TLS and enhancing cell tolerance to DNA damage, subunits REV7 and REV3 (3). which parallels SOS responses in bacteria. Cells from XP-variant (XP-V) patients were originally de- scribed as proficient in lesion removal, but deficient inDNA
*To whom correspondence should be addressed. Tel: +55 11 3091 7499; Fax: +55 11 3091 7354; Email: [email protected] †Present address: Leticia K. Lerner, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.