Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Checkpoint Kinase 1
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Cyclin A / genetics
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Cyclin A / metabolism
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Cyclin E / metabolism*
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Cyclin-Dependent Kinase 2 / metabolism
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DNA Damage / drug effects
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DNA Damage / physiology
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DNA Damage / radiation effects
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DNA Replication / drug effects
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DNA Replication / physiology*
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DNA Replication / radiation effects
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G1 Phase / drug effects
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G1 Phase / physiology
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G1 Phase / radiation effects
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HeLa Cells
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Humans
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Mitomycin / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Protein Stability / drug effects
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Protein Stability / radiation effects
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S Phase / drug effects
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S Phase / physiology*
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S Phase / radiation effects
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Ultraviolet Rays
Substances
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CDC6 protein, human
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Cell Cycle Proteins
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Cyclin A
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Cyclin E
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NBN protein, human
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Nuclear Proteins
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Nucleic Acid Synthesis Inhibitors
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Mitomycin
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Protein Kinases
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2