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

Carsten Müller-Tidow, Ping Ji, Sven Diederichs, Jenny Potratz, Nicole Bäumer, Gabriele Köhler, Thomas Cauvet, Chunaram Choudary, Tiffany Van Der Meer, Wan Yu Iris Chan, Conrad Nieduszynski, William H. Colledge, Mark Carrington, H. Phillip Koeffler, Anja Restle, Lisa Wiesmüller, Joëlle Sobczak-Thépot, Wolfgang E. Berdel, Hubert Serve

Research output: Contribution to journalArticle

82 Scopus citations

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 γ-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 (US)
Pages (from-to)8917-8928
Number of pages12
JournalMolecular and cellular biology
Volume24
Issue number20
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Müller-Tidow, C., Ji, P., Diederichs, S., Potratz, J., Bäumer, N., Köhler, G., Cauvet, T., Choudary, C., Van Der Meer, T., Chan, W. Y. I., Nieduszynski, C., 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