Nucleotide excision repair DNA synthesis by excess DNA polymerase beta: a potential source of genetic instability in cancer cells.
The nucleotide excision repair pathway contributes to genetic stability by removing a wide range of DNA damage through an error-free reaction. When the lesion is located, the altered strand is incised on both sides of the lesion and a damaged oligonucleotide excised. A repair patch is then synthesized and the repaired strand is ligated. It is assumed that only DNA polymerases delta and/or epsilon participate to the repair DNA synthesis step. Using UV and cisplatin-modified DNA templates, we measured in vitro that extracts from cells overexpressing the error-prone DNA polymerase beta exhibited a five- to sixfold increase of the ultimate DNA synthesis activity compared with control extracts and demonstrated the specific involvement of Pol beta in this step. By using a 28 nt gapped, double-stranded DNA substrate mimicking the product of the incision step, we showed that Pol beta is able to catalyze strand displacement downstream of the gap. We discuss these data within the scope of a hypothesis previously presented proposing that excess error-prone Pol beta in cancer cells could perturb the well-defined specific functions of DNA polymerases during error-free DNA transactions.
Canitrot
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Groupe 'Instabilité génétique et cancer', Groupe 'Toxico-résistance', Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, 31077 Toulouse cedex 4, France. cazaux@ipbs.fr
Hoffmann
J S
JS
Calsou
P
P
Hayakawa
H
H
Salles
B
B
Cazaux
C
C
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002457:Cell Extracts; D006224:Cricetinae; D019951:DNA Polymerase beta / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D014407:Tumor Cells, Cultured
D002457:Cell Extracts; D004273:DNA, Neoplasm; D019951:DNA Polymerase beta