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PMID: 15456866 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 24 ·No. 20 ·2004-10-00 ·Pages 8917-28

Müller-Tidow C, Ji P, Diederichs S, Potratz J, Bäumer N, Köhler G, Cauvet T, Choudary C, van der Meer T, Chan WY, Nieduszynski C, Colledge WH, Carrington M, Koeffler HP, Restle A, Wiesmüller L, Sobczak-Thépot J, Berdel WE, Serve H

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.

MeSH Terms
Animals Antigens, Nuclear/genetics,metabolism CDC2-CDC28 Kinases/genetics,metabolism Cells, Cultured Cyclin A/genetics,metabolism Cyclin A1 Cyclin-Dependent Kinase 2 DNA/metabolism,radiation effects DNA Damage DNA Repair DNA-Binding Proteins/genetics,metabolism Fibroblasts/cytology,metabolism,radiation effects Gamma Rays Gene Expression Regulation Hematopoietic Stem Cells Humans Ku Autoantigen Macromolecular Substances Male Mice Mice, Inbred BALB C Mice, Knockout Promoter Regions, Genetic Random Allocation Recombination, Genetic Tumor Suppressor Protein p53/genetics,metabolism Two-Hybrid System Techniques Ultraviolet Rays
Chemicals
Antigens, Nuclear CCNA1 protein, human Ccna1 protein, mouse Cyclin A Cyclin A1 DNA-Binding Proteins Macromolecular Substances Tumor Suppressor Protein p53 DNA CDC2-CDC28 Kinases CDK2 protein, human Cdk2 protein, mouse Cyclin-Dependent Kinase 2 Xrcc6 protein, human Xrcc6 protein, mouse Ku Autoantigen
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Müller-Tidow Carsten
Dept. of Medicine, Hematology/Oncology, University of Münster, Domagkstr. 3, 48129 Münster, Germany. [email protected]
Ji Ping
Diederichs Sven
Potratz Jenny
Bäumer Nicole
Köhler Gabriele
Cauvet Thomas
Choudary Chunaram
van der Meer Tiffany
Chan Wan-Yu Iris
Nieduszynski Conrad
Colledge William H
Carrington Mark
Koeffler H Phillip
Restle Anja
Wiesmüller Lisa
Sobczak-Thépot Joëlle
Berdel Wolfgang E
Serve Hubert
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.20.8917-8928.2004
Email
[email protected]
Published
2004-10-00
Pages
8917-28
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC517883
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.20.8917-8928.2004 PMC Full Text View journal details
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