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

Dexi Chen, Zhiyong Yu, Zhiyi Zhu, Charles Lopez

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)15381-15389
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume283
    Issue number22
    DOIs
    StatePublished - May 30 2008

    Fingerprint

    DNA Repair
    Repair
    Genes
    X-Rays
    X rays
    DNA
    Methyl Methanesulfonate
    Fibroblasts
    Embryonic Structures
    Cricetulus
    Luciferases
    Ovary
    E2F1 Transcription Factor
    Apoptosis
    Genomic Instability
    Cells
    S Phase
    DNA Damage
    Transcription
    Binding Sites

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology

    Cite this

    E2F1 regulates the base excision repair gene XRCC1 and promotes DNA repair. / Chen, Dexi; Yu, Zhiyong; Zhu, Zhiyi; Lopez, Charles.

    In: Journal of Biological Chemistry, Vol. 283, No. 22, 30.05.2008, p. 15381-15389.

    Research output: Contribution to journalArticle

    Chen, Dexi ; Yu, Zhiyong ; Zhu, Zhiyi ; Lopez, Charles. / E2F1 regulates the base excision repair gene XRCC1 and promotes DNA repair. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 22. pp. 15381-15389.
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    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.",
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