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Mol Cell Biol. 2008 Dec;28(23):7245-58. doi: 10.1128/MCB.01085-08. Epub 2008 Sep 22.

Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability.

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  • 1Department of Cancer Biology, The Abramson Family Cancer Research Institute, 454 BRB II/III, Philadelphia, PA 19104-6140, USA.

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 GSK3beta, which in turn mediate cyclin D1 phosphorylation. Phosphorylated cyclin D1 is targeted for proteasomal degradation after ubiquitylation by SCF(Fbx4-alphaBcrystallin). 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.

PMID:
18809569
[PubMed - indexed for MEDLINE]
PMCID:
PMC2593367
Free PMC Article
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