Abstract
Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins / metabolism*
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / physiology*
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Cell Division
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Checkpoint Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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DNA Damage
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DNA-Binding Proteins / physiology*
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G2 Phase
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Genes, p53*
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Humans
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Mice
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NIH 3T3 Cells
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Phosphorylation
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / physiology*
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Repressor Proteins / metabolism*
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Suppressor Proteins / physiology*
Substances
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AATF protein, human
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Repressor Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Checkpoint Kinase 2
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK2 protein, human
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases