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

• Published in: Nucleic acids research 2017-02, Vol.45 (3), p.1270-1280
• Main Authors: Lerner, Leticia K, Francisco, Guilherme, Soltys, Daniela T, Rocha, Clarissa R R, Quinet, Annabel, Vessoni, Alexandre T, Castro, Ligia P, David, Taynah I P, Bustos, Silvina O, Strauss, Bryan E, Gottifredi, Vanesa, Stary, Anne, Sarasin, Alain, Chammas, Roger, Menck, Carlos F M
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Cancer; Cell Line; Cell Survival; Cellular Biology; Chromatin; Chromatin - metabolism; DNA; DNA - biosynthesis; DNA Repair; DNA Repair - genetics; DNA Repair - radiation effects; DNA Replication; DNA Replication - radiation effects; DNA-Directed DNA Polymerase; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Dose-Response Relationship, Radiation; Fibroblasts; Fibroblasts - radiation effects; Gene Expression Regulation; Gene Expression Regulation - radiation effects; Genome Integrity, Repair and; Humans; Life Sciences; Tumor Suppressor Protein p53; Tumor Suppressor Protein p53 - metabolism; Ultraviolet Rays
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkw1196

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.