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Mutagenesis Advance Access originally published online on January 31, 2007
Mutagenesis 2007 22(3):183-188; doi:10.1093/mutage/gel070
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© The Author 2007. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Overexpression of DNA polymerase ß results in an increased rate of frameshift mutations during base excision repair

Katie Chan, Sue Houlbrook1, Qiu-Mei Zhang2, Mark Harrison3, Ian D. Hickson1 and Grigory L. Dianov*

Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD, UK 1Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK 2Laboratory of Radiation Biology, Graduate School of Sciences, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan 3Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts, EN6 3LD, UK

DNA polymerase ß (Pol ß) is important for the base excision repair (BER) pathway. Overexpression of Pol ß is frequently found in cancer cells and is thought to be associated with tumorigenesis. In this study, we examined BER fidelity in extracts derived from a human lymphoblastoid cell line that overexpresses Pol ß compared to normal control cells. Using an in vitro mutagenesis assay, we found an increased rate of frameshift mutations arising during DNA repair in whole-cell extracts derived from the Pol ß-overexpressing cells. We demonstrate that the addition of excess Pol ß to a control cell extract enhances the mutagenic potential of the extract. Furthermore, using cell extracts and purified Pol ß, we demonstrate that the mechanism of frameshift formation involves slippage of Pol ß during the one-nucleotide gap-filling step of BER and that this slippage is fixed by strand-displacement synthesis stimulated by an excess of Pol ß.

* To whom correspondence should be addressed. Tel: +44 1235 841134; Fax: +44 1235 841200; Email: g.dianov{at}har.mrc.ac.uk

Received on November 7, 2006; revised on December 12, 2006; accepted on December 13, 2006.


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