Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals

Sigal Shachar, Omer Ziv, Sharon Avkin, Sheera Adar, John Wittschieben, Thomas Reißner, Stephen Chaney, Errol C. Friedberg, Zhigang Wang, Thomas Carell, Nicholas Geacintov, Zvi Livneh

Research output: Contribution to journalArticle

196 Scopus citations

Abstract

DNA replication across blocking lesions occurs by translesion DNA synthesis (TLS), involving a multitude of mutagenic DNA polymerases that operate to protect the mammalian genome. Using a quantitative TLS assay, we identified three main classes of TLS in human cells: two rapid and error-free, and the third slow and error-prone. A single gene, REV3L, encoding the catalytic subunit of DNA polymerase ζ (polζ), was found to have a pivotal role in TLS, being involved in TLS across all lesions examined, except for a TT cyclobutane dimer. Genetic epistasis siRNA analysis indicated that discrete two-polymerase combinations with polζ dictate error-prone or error-free TLS across the same lesion. These results highlight the central role of polζ in both error-prone and error-free TLS in mammalian cells, and show that bypass of a single lesion may involve at least three different DNA polymerases, operating in different two-polymerase combinations.

Original languageEnglish (US)
Pages (from-to)383-393
Number of pages11
JournalEMBO Journal
Volume28
Issue number4
DOIs
StatePublished - Feb 18 2009

Keywords

  • Carcinogenesis
  • DNA damage
  • DNA repair
  • Lesion bypass
  • Mutagenesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Shachar, S., Ziv, O., Avkin, S., Adar, S., Wittschieben, J., Reißner, T., Chaney, S., Friedberg, E. C., Wang, Z., Carell, T., Geacintov, N., & Livneh, Z. (2009). Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO Journal, 28(4), 383-393. https://doi.org/10.1038/emboj.2008.281