Published online 14 April 2005
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APE1-dependent repair of DNA single-strand breaks containing 3'-end 8-oxoguanine
MRC Radiation and Genome Stability Unit, Harwell Oxfordshire OX11 0RD, UK
*To whom correspondence should be addressed. Tel: +44 1235 841 134; Fax: +44 1235 841 200; Email: g.dianov{at}har.mrc.ac.uk
Received February 16, 2005. Revised March 29, 2005. Accepted March 29, 2005.
DNA single-strand breaks containing 3'-8-oxoguanine (3'-8-oxoG) ends can arise as a consequence of ionizing radiation and as a result of DNA polymerase infidelity by misincorporation of 8-oxodGMP. In this study we examined the mechanism of repair of 3'-8-oxoG within a single-strand break using purified base excision repair enzymes and human whole cell extracts. We find that 3'-8-oxoG inhibits ligation by DNA ligase III
or DNA ligase I, inhibits extension by DNA polymerase ß and that the lesion is resistant to excision by DNA glycosylases involved in the repair of oxidative lesions in human cells. However, we find that purified human AP-endonuclease 1 (APE1) is able to remove 3'-8-oxoG lesions. By fractionation of human whole cell extracts and immunoprecipitation of fractions containing 3'-8-oxoG excision activity, we further demonstrate that APE1 is the major activity involved in the repair of 3'-8-oxoG lesions in human cells and finally we reconstituted repair of the 3'-8-oxoG-containing oligonucleotide duplex with purified human enzymes including APE1, DNA polymerase ß and DNA ligase III.
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