The cyclin A1-CDK2 complex regulates DNA double-strand break repair.

J. Müller-Tidow, P. Ji, S. Diederichs, J. Potratz, N. Bäumer, G. Köhler, T. Cauvet, C. Choudary, T. Van Der Meer, W. Y. Chan, Conrad A Nieduszynski, W. H. Colledge, M. Carrington, H. P. Koeffler, A. Restle, L. Wiesmüller, J. Sobczak-Thépot, W. E. Berdel, H. Serve

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    Abstract

    Vertebrates express two A-type cyclins; both associate with and activate the CDK2 protein kinase. Cyclin A1 is required in the male germ line, but its molecular functions are incompletely understood. We observed specific induction of cyclin A1 expression and promoter activity after UV and gamma-irradiation which was mediated by p53. cyclin A1(-/-) cells showed increased radiosensitivity. To unravel a potential role of cyclin A1 in DNA repair, we performed a yeast triple hybrid screen and identified the Ku70 DNA repair protein as a binding partner and substrate of the cyclin A1-CDK2 complex. DNA double-strand break (DSB) repair was deficient in cyclin A1(-/-) cells. Further experiments indicated that A-type cyclins activate DNA DSB repair by mechanisms that depend on CDK2 activity and Ku proteins. Both cyclin A1 and cyclin A2 enhanced DSB repair by homologous recombination, but only cyclin A1 significantly activated nonhomologous end joining. DNA DSB repair was specific for A-type cyclins because cyclin E was ineffective. These findings establish a novel function for cyclin A1 and CDK2 in DNA DSB repair following radiation damage.

    Original languageEnglish
    Pages (from-to)8917-8928
    Number of pages12
    JournalMolecular and Cellular Biology
    Volume24
    Issue number20
    DOIs
    Publication statusPublished - Oct 2004

    Keywords

    • DEPENDENT PROTEIN-KINASE
    • ACUTE MYELOID-LEUKEMIA
    • P14(ARF) TUMOR-SUPPRESSOR
    • CELL LINES
    • HEMATOPOIETIC-CELLS
    • IONIZING-RADIATION
    • BINDING PROTEIN
    • MAMMALIAN-CELLS
    • GENE-EXPRESSION
    • A1 PROMOTER

    Cite this

    Müller-Tidow, J., Ji, P., Diederichs, S., Potratz, J., Bäumer, N., Köhler, G., Cauvet, T., Choudary, C., Van Der Meer, T., Chan, W. Y., Nieduszynski, C. A., Colledge, W. H., Carrington, M., Koeffler, H. P., Restle, A., Wiesmüller, L., Sobczak-Thépot, J., Berdel, W. E., & Serve, H. (2004). The cyclin A1-CDK2 complex regulates DNA double-strand break repair. Molecular and Cellular Biology, 24(20), 8917-8928. https://doi.org/10.1128/MCB.24.20.8917-8928.2004