Cyclin E is stabilized in response to replication fork barriers leading to prolonged S phase arrest.
Cyclin E is a regulator of cyclin-dependent protein kinases (Cdks) and is involved in mediating the cell cycle transition from G(1) to S phase. Here, we describe a novel function for cyclin E in the long term maintenance of checkpoint arrest in response to replication barriers. Exposure of cells to mitomycin C or UV irradiation, but not ionizing radiation, induces stabilization of cyclin E. Stabilization of cyclin E reduces the activity of Cdk2-cyclin A, resulting in a slowing of S phase progression and arrest. In addition, cyclin E is shown to be required for stabilization of Cdc6, which is required for activation of Chk1 and the replication checkpoint pathway. Furthermore, the stabilization of cyclin E in response to replication fork barriers depends on ATR, but not Nbs1 or Chk1. These results indicate that in addition to its well studied role in promoting cell cycle progression, cyclin E also has a role in regulating cell cycle arrest in response to DNA damage.
Lu
Xiaoyan
X
Department of Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Liu
Jia
J
Legerski
Randy J
RJ
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects / Q000528:radiation effects; D016196:S Phase / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays
C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; C112156:NBN protein, human; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2