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

Mol Cell Biol. 2004 Oct;24(20):8917-28. doi: 10.1128/MCB.24.20.8917-8928.2004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism
  • CDC2-CDC28 Kinases / genetics
  • CDC2-CDC28 Kinases / metabolism*
  • Cells, Cultured
  • Cyclin A / genetics
  • Cyclin A / metabolism*
  • Cyclin A1
  • Cyclin-Dependent Kinase 2
  • DNA / metabolism*
  • DNA / radiation effects*
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fibroblasts / 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
  • Tumor Suppressor Protein p53 / metabolism
  • Two-Hybrid System Techniques
  • Ultraviolet Rays

Substances

  • 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