Two‐polymerase mechanisms dictate error‐free and error‐prone translesion DNA synthesis in mammals |
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Authors: | 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 |
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Affiliation: | 1. Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel;2. Department of Pharmacology, University of Pittsburgh Medical School and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;3. Department of Chemistry and Biochemistry, Ludwig‐Maximilians‐University Munich, München, Germany;4. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA;5. Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA;6. Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA;7. Chemistry Department, New York University, New York, NY, USA |
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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. |
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Keywords: | carcinogenesis DNA damage DNA repair lesion bypass mutagenesis |
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