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Nucleic Acids Research Advance Access published online on May 25, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp422
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic

Sophie Bellon1, Naoya Shikazono2, Siobhan Cunniffe1, Martine Lomax1 and Peter O’Neill1,*

1DNA Damage Group, Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK and 2Japan Atomic Energy Agency, Advanced Research Science Centre, 2-4 Shirakata-Shirane, Tokai-mura, Ibaraki 319-1195, Japan

*To whom correspondence should be addressed. Tel: +44 (0)1865 617326; Fax: +44 (0)1865 617355; Email: peter.oneill{at}rob.ox.ac.uk

Received February 19, 2009. Revised May 1, 2009. Accepted May 10, 2009.

Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. The potential for genetic change arising from the effects of clustered damage sites containing combinations of AP sites, 8-oxo-7,8-dihydroguanine (8-oxoG) or 5,6-dihydrothymine is high. To date clusters containing a DNA base lesion that is a strong block to replicative polymerases, have not been explored. Since thymine glycol (Tg) is non-mutagenic but a strong block to replicative polymerases, we have investigated whether clusters containing Tg are highly mutagenic or lead to potentially cytotoxic lesions, when closely opposed to either 8-oxoG or an AP site. Using a bacterial plasmid-based assay and repair assays using cell extracts or purified proteins, we have shown that DNA double-strand breaks (DSBs) arise when Tg is opposite to an AP site, either through attempted base excision repair or at replication. In contrast, 8-oxoG opposite to Tg in a cluster ‘protects’ against DSB formation but does enhance the mutation frequency at the site of 8-oxoG relative to that at a single 8-oxoG, due to the decisive role of endonucleases in the initial stages of processing Tg/8-oxoG clusters, removing Tg to give an intermediate with an abasic site or single-strand break.


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