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Nucleic Acids Research 2005 33(1):280-288; doi:10.1093/nar/gki168
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Published online 12 January 2005

© 2005, the authors Nucleic Acids Research, Vol. 33 No. 1 © Oxford University Press 2005; all rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use permissions, please contact journals.permissions{at}oupjournals.org.

Article

The accumulation of MMS-induced single strand breaks in G1 phase is recombinogenic in DNA polymerase ß defective mammalian cells

Barbara Pascucci1,2, Maria Teresa Russo2, Marco Crescenzi2, Margherita Bignami2 and Eugenia Dogliotti2,*

1 Istituto di Cristallografia, CNR, Sezione di Roma PO Box 10, 00016 Monterotondo Stazione, Roma, Italy 2 Department of Environment and Primary Prevention, Istituto Superiore di Sanità Viale Regina Elena 299, 00161 Roma, Italy

*To whom correspondence should be addressed. Tel: +39 06 49902580; Fax: +39 06 49903650; Email: dogliott{at}iss.it

Received September 10, 2004. Revised November 26, 2004. Accepted December 15, 2004.

DNA polymerase (Pol) ß null mouse embryonic fibroblasts provide a useful cell system to investigate the effects of alterations in base excision repair (BER) on genome stability. These cells are characterized by hypersensitivity to the cytotoxic effects of methyl methanesulfonate (MMS) and by decreased repair of the MMS-induced DNA single strand breaks (SSB). Here, we show that, in the absence of Pol ß, SSB accumulate in G1 phase cells, accompanied by the formation of proliferating cell nuclear antigen foci in the nuclei. When replicating Pol ß null cells are treated with MMS, a rapid phosphorylation of histone H2AX is detected in the nuclei of S phase cells, indicating that double strand breaks (DSB) are formed in response to unrepaired SSB. This is followed by relocalization within the nuclei of Rad51 protein, which is essential for homologous recombination (HR). These findings are compatible with a model where, in mammalian cells, unrepaired SSB produced during BER are substrates for the HR pathway via DSB formation. This is an example of a coordinated effort of two different repair pathways, BER and HR, to protect mammalian cells from alkylation-induced cytotoxicity.


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