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

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 th...

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Bibliographic Details
Published in:The EMBO journal Vol. 28; no. 4; pp. 383 - 393
Main Authors: Shachar, Sigal, Ziv, Omer, Avkin, Sharon, Adar, Sheera, Wittschieben, John, Reißner, Thomas, Chaney, Stephen, Friedberg, Errol C, Wang, Zhigang, Carell, Thomas, Geacintov, Nicholas, Livneh, Zvi
Format: Journal Article
Language:English
Published: Chichester, UK John Wiley & Sons, Ltd 18.02.2009
Nature Publishing Group UK
Springer Nature B.V
Nature Publishing Group
Subjects:
Animals
carcinogenesis
Catalysis
Cell Line, Tumor
Cellular biology
Deoxyribonucleic acid
Dimerization
DNA
DNA - chemistry
DNA - metabolism
DNA Damage
DNA polymerase
DNA repair
DNA Replication
DNA-Directed DNA Polymerase - chemistry
DNA-Directed DNA Polymerase - metabolism
Epistasis, Genetic
Genomics
Humans
Kinetics
lesion bypass
Lesions
Mammals
Mice
Molecular biology
Mutagenesis
Pyrimidine Dimers - chemistry
RNA, Small Interfering - metabolism
Xeroderma Pigmentosum Group A Protein - metabolism
carcinogenesis
DNA repair
mutagenesis
DNA damage
lesion bypass
ISSN:0261-4189, 1460-2075, 1460-2075
Online Access:Get full text
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Summary: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.
Bibliography:ArticleID:EMBJ2008281
istex:B964CBF19EFB01776736441F4889B17FF5998663
ark:/67375/WNG-5STT2SMS-K
Supplementary Information
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SourceType-Scholarly Journals-1
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ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1038/emboj.2008.281