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Nucleic Acids Research 2005 33(12):3799-3811; doi:10.1093/nar/gki681
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Published online 11 July 2005

© The Author 2005. Published by Oxford University Press. 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, please contact journals.permissions{at}oupjournals.org

Article

Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks

Cecilia Lundin1, Matthew North2, Klaus Erixon1, Kevin Walters3, Dag Jenssen1, Alastair S. H. Goldman2 and Thomas Helleday1,4,*

1Department of Genetics, Microbiology and Toxicology, Stockholm University Svante Arrhenius väg 16, S-106 91 Stockholm, Sweden 2Department of Molecular Biology and Biotechnology, University of Sheffield Sheffield S10 2TN, UK 3Mathematical Modelling and Genetic Epidemiology, University of Sheffield Sheffield S10 2TN, UK 4The Institute for Cancer Studies, Division of Genomic Medicine, University of Sheffield Sheffield S10 2TN, UK

*To whom correspondence should be addressed at Department of Genetics, Microbiology and Toxicology, Stockholm University, Svante Arrhenius väg 16, S-106 91 Stockholm, Sweden. Tel: +46 8 16 29 14; Fax: +46 8 16 43 15; Email: helleday{at}gmt.su.se. The authors wish it to be known that Dr A. Goldman is considered as joint senior (last) author (contact details: Tel: +44 114 222 2779; Fax: +44 114 272 8697; Email: a.goldman{at}sheffield.ac.uk)

Received March 23, 2005. Revised June 13, 2005. Accepted June 13, 2005.

Homologous recombination (HR) deficient cells are sensitive to methyl methanesulfonate (MMS). HR is usually involved in the repair of DNA double-strand breaks (DSBs) in Saccharomyces cerevisiae implying that MMS somehow induces DSBs in vivo. Indeed there is evidence, based on pulsed-field gel electrophoresis (PFGE), that MMS causes DNA fragmentation. However, the mechanism through which MMS induces DSBs has not been demonstrated. Here, we show that DNA fragmentation following MMS treatment, and detected by PFGE is not the consequence of production of cellular DSBs. Instead, DSBs seen following MMS treatment are produced during sample preparation where heat-labile methylated DNA is converted into DSBs. Furthermore, we show that the repair of MMS-induced heat-labile damage requires the base excision repair protein XRCC1, and is independent of HR in both S.cerevisiae and mammalian cells. We speculate that the reason for recombination-deficient cells being sensitive to MMS is due to the role of HR in repair of MMS-induced stalled replication forks, rather than for repair of cellular DSBs or heat-labile damage.


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