Nucleic Acids Research Advance Access originally published online on April 27, 2007
Nucleic Acids Research 2007 35(10):3355-3366; doi:10.1093/nar/gkm190
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Nucleic Acids Research, 2007, Vol. 35, No. 10 3355-3366
© 2007 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.
Molecular Biology |
Interplay between DNA N-glycosylases/AP lyases at multiply damaged sites and biological consequences
1CNRS-IC UMR 2027, Institut Curie, Centre Universitaire, F-91405 Orsay, France and 2Laboratoire "Lésions des Acides Nucléiques"/Service de Chimie Inorganique et Biologique UMR E3 CEA-UJF/Département de Recherche Fondamentale sur la Matière Condensée, CEA-Grenoble, F-38054 Grenoble Cedex 9, France
*To whom correspondence should be addressed. Tel: +33 1 6986 7187; Fax: +33 1 6986 9429; Email: Evelyne.Sage{at}curie.u-psud.fr
Received February 2, 2007. Revised February 28, 2007. Accepted March 16, 2007.
Evidence has emerged that repair of clustered DNA lesions may be compromised, possibly leading to the formation of double-strand breaks (DSB) and, thus, to deleterious events. The first repair event occurring at a multiply damaged site (MDS) is of major importance and will largely contribute to the hazardousness of MDS. Here, using protein extracts from wild type or hOGG1-overexpressing Chinese hamster ovary cells, we investigated the initial incision rate at base damage and the formation of repair intermediates in various complex MDS. These MDS comprise a 1 nt gap and 3–4 base damage, including 8-oxoguanine (oG) and 5-hydroxyuracil (hU). We report a hierarchy in base excision that mainly depends on the nature and the distribution of the damage. We also show that excision at both oG and hU, and consequently DSB formation, can be modulated by hOGG1 overexpression. Anyhow, for all the MDS analyzed, DSB formation is limited, due to impaired base excision. Interestingly, repair intermediates contain a short single-stranded region carrying a potentially mutagenic base damage. This in vitro study provides new insight into the processing of MDS and suggests that repair intermediates resulting from the processing of such MDS are rather mutagenic than toxic.
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