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J Biol Chem. 2008 May 30;283(22):15381-9. doi: 10.1074/jbc.M710296200. Epub 2008 Mar 17.

E2F1 regulates the base excision repair gene XRCC1 and promotes DNA repair.

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  • 1Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA.

Abstract

The E2F1 transcription factor activates S-phase-promoting genes, mediates apoptosis, and stimulates DNA repair through incompletely understood mechanisms. XRCC1 (x-ray repair cross-complementing group 1) protein is important for efficient single strand break/base excision repair. Although both damage and proliferative signals increase XRCC1 levels, the mechanisms regulating XRCC1 transcription remain unclear. To study these upstream mechanisms, the XRCC1 promoter was cloned into a luciferase reporter. Ectopic expression of wild-type E2F1, but not an inactive mutant E2F1(132E), activated the XRCC1 promoter-luciferase reporter, and deletion of predicted E2F1 binding sites in the promoter attenuated E2F1-induced activation. Endogenous XRCC1 expression increased in cells conditionally expressing wild-type, but not mutant E2F1, and methyl methanesulfonate-induced DNA damage stimulated XRCC1 expression in E2F1(+/+) but not E2F1(-/-) mouse embryo fibroblasts (MEFs). Additionally, E2F1(-/-) MEFs displayed attenuated DNA repair after methyl methanesulfonate-induced damage compared with E2F1(+/+) MEFs. Moreover, Chinese hamster ovary cells with mutant XRCC1 (EM9) were more sensitive to E2F1-induced apoptosis compared with Chinese hamster ovary cells with wild-type XRCC1 (AA8). These results provide new mechanistic insight into the role of the E2F pathway in maintaining genomic stability.

PMID:
18348985
[PubMed - indexed for MEDLINE]
PMCID:
PMC2397471
Free PMC Article
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