Journal
EMBO JOURNAL
Volume 28, Issue 4, Pages 383-393Publisher
WILEY
DOI: 10.1038/emboj.2008.281
Keywords
carcinogenesis; DNA damage; DNA repair; lesion bypass; mutagenesis
Categories
Funding
- Flight Attendant Medical Research Institute, Florida, USA
- Israel Science Foundation [564/04]
- MD Moross Institute for Cancer Research
- NIH, USA [CA 099194, CA112412, CA92528, ES11354]
- Richard D Wood, University of Pittsburgh [CA098675]
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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 zeta (pol zeta), 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 pol zeta dictate error-prone or error-free TLS across the same lesion. These results highlight the central role of pol zeta 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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