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Article

Genotoxic Stress-Induced Cyclin D1 Phosphorylation and Proteolysis Are Required for Genomic Stability

, , , , &
Pages 7245-7258 | Received 10 Jul 2008, Accepted 14 Sep 2008, Published online: 27 Mar 2023
 

Abstract

While mitogenic induction of cyclin D1 contributes to cell cycle progression, ubiquitin-mediated proteolysis buffers this accumulation and prevents aberrant proliferation. Because the failure to degrade cyclin D1 during S-phase triggers DNA rereplication, we have investigated cellular regulation of cyclin D1 following genotoxic stress. These data reveal that expression of cyclin D1 alleles refractory to phosphorylation- and ubiquitin-mediated degradation increase the frequency of chromatid breaks following DNA damage. Double-strand break-dependent cyclin D1 degradation requires ATM and GSK3β, which in turn mediate cyclin D1 phosphorylation. Phosphorylated cyclin D1 is targeted for proteasomal degradation after ubiquitylation by SCFFbx4-αBcrystallin. Loss of Fbx4-dependent degradation triggers radio-resistant DNA synthesis, thereby sensitizing cells to S-phase-specific chemotherapeutic intervention. These data suggest that failure to degrade cyclin D1 compromises the intra-S-phase checkpoint and suggest that cyclin D1 degradation is a vital cellular response necessary to prevent genomic instability following genotoxic insult.

ACKNOWLEDGMENTS

We thank P. Sicinski for the D1−/− fibroblasts and Roger Greenberg for control and Chk2 siRNA.

This study was supported by CA93237 (National Institutes of Health) and a Leukemia and Lymphoma Scholar award (J.A.D.) and the Pew Foundation in the Biomedical Sciences and the Department of Pathology of the Children's Hospital of Philadelphia (C.H.B.).

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