Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells.
Genome lesions trigger biological responses that help cells manage damaged DNA, improving cell survival. Pol eta is a translesion synthesis (TLS) polymerase that bypasses lesions that block replicative polymerases, avoiding continued stalling of replication forks, which could lead to cell death. p53 also plays an important role in preventing cell death after ultraviolet (UV) light exposure. Intriguingly, we show that p53 does so by favoring translesion DNA synthesis by pol eta. In fact, the p53-dependent induction of pol eta in normal and DNA repair-deficient XP-C human cells after UV exposure has a protective effect on cell survival after challenging UV exposures, which was absent in p53- and Pol H-silenced cells. Viability increase was associated with improved elongation of nascent DNA, indicating the protective effect was due to more efficient lesion bypass by pol eta. This protection was observed in cells proficient or deficient in nucleotide excision repair, suggesting that, from a cell survival perspective, proper bypass of DNA damage can be as relevant as removal. These results indicate p53 controls the induction of pol eta in DNA damaged human cells, resulting in improved TLS and enhancing cell tolerance to DNA damage, which parallels SOS responses in bacteria.
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Leticia K
LK
Lerner
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of São Paulo-ICESP, São Paulo, Brazil.
Guilherme
G
Francisco
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Daniela T
DT
Soltys
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Clarissa R R
CR
Rocha
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Annabel
A
Quinet
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Alexandre T
AT
Vessoni
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Ligia P
LP
Castro
Viral Vector Laboratory, Heart Institute, University of São Paulo, São Paulo, Brazil.
Taynah I P
TI
David
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of São Paulo-ICESP, São Paulo, Brazil.
Silvina O
SO
Bustos
Viral Vector Laboratory, Heart Institute, University of São Paulo, São Paulo, Brazil.
Bryan E
BE
Strauss
Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
Vanesa
V
Gottifredi
CNRS-UMR8200, Université Paris-Sud, Institut de Cancérologie Gustave Roussy, Villejuif, France.
Anne
A
Stary
CNRS-UMR8200, Université Paris-Sud, Institut de Cancérologie Gustave Roussy, Villejuif, France.
Alain
A
Sarasin
Department of Center for Translational Oncology Cellular, Biology Group, Center for Translational Oncology, Cancer Institute of the State of São Paulo-ICESP, São Paulo, Brazil.
Roger
R
Chammas
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Carlos F M
CF
Menck
D002460:Cell Line; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004261:DNA Replication / Q000528:radiation effects; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
D002843:Chromatin; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases