Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells

Leticia K. Lerner (1) , Guilherme Francisco (2) , Daniela T. Soltys (3) , Clarissa R. R. Rocha (1) , Annabel Quinet (1) , Alexandre T. Vessoni (1) , Ligia P. Castro (1) , Taynah I. P. David (1) , Silvina O. Bustos (2) , Bryan E. Strauss (1) , Vanesa Gottifredi (4) , Anne Stary (5) , Alain Sarasin (5) , Roger Chammas (2) , Carlos F. M. Menck (1)

1 USP - Universidade de São Paulo = University of São Paulo
2 ICESP - Instituto do Câncer do Estado = Cancer Institute of the State of São Paulo
3 Institute of Chemistry [University of São Paulo] | Instituto de Química [Universidade de São Paulo]
4 Fundación Instituto Leloir [Buenos Aires]
5 IGC - Intégrité du génome et cancers

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.

Domaines: Biochimie, Biologie Moléculaire; Biologie cellulaire; Cancer

Leticia K. Lerner, Guilherme Francisco, Daniela T. Soltys, Clarissa R. R. Rocha, Annabel Quinet, et al.. Predominant role of DNA polymerase eta and p53-dependent translesion synthesis in the survival of ultraviolet-irradiated human cells. Nucleic Acids Research, 2017, 45 (3), pp.1270-1280. ⟨10.1093/nar/gkw1196⟩. ⟨hal-03679015⟩