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The Cyclin A1-CDK2 Complex Regulates DNA Double-Strand Break Repair

Carsten Müller-Tidow,^1,* Ping Ji,^1, Sven Diederichs,¹ Jenny Potratz,¹ Nicole Bäumer,¹ Gabriele Köhler,² Thomas Cauvet,¹ Chunaram Choudary,¹ Tiffany van der Meer,³ Wan-Yu Iris Chan,⁴ Conrad Nieduszynski,⁴ William H. Colledge,³ Mark Carrington,⁴ H. Phillip Koeffler,⁵ Anja Restle,⁶ Lisa Wiesmüller,⁶ Joëlle Sobczak-Thépot,⁷ Wolfgang E. Berdel,¹ and Hubert Serve¹

Hematology/Oncology, Department of Medicine,¹ Gerhard Domagk Institute of Pathology, University of Münster, Münster,² Gynaecological Oncology, Universitätsfrauenklinik, Ulm, Germany,⁶ Department of Physiology,³ Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom,⁴ Division of Hematology/Oncology, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, California,⁵ INSERM U370, Faculté de Médecine Necker, Institut Pasteur/Necker, Paris, France⁷

Received 22 March 2004/ Returned for modification 27 April 2004/ Accepted 21 July 2004

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 -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.

K.M.-T. and P.J. contributed equally.

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