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

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.
Authors	Laura L Pontano, Priya Aggarwal, Olena Barbash, Eric J Brown, Craig H Bassing, J Alan Diehl
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 28 Issue 23 Pg. 7245-58 (Dec 2008) ISSN: 1098-5549 [Electronic] United States
PMID	18809569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Cell Cycle Proteins DNA-Binding Proteins Tumor Suppressor Proteins Cyclin D1 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases Glycogen Synthase Kinase 3 Proteasome Endopeptidase Complex
Topics	3T3 Cells Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins Cell Line Cyclin D1 (genetics, metabolism) DNA Damage DNA-Binding Proteins Genomic Instability Glycogen Synthase Kinase 3 Humans Mice Phosphorylation Proteasome Endopeptidase Complex (metabolism) Protein Processing, Post-Translational Protein Serine-Threonine Kinases S Phase Tumor Suppressor Proteins Ubiquitination

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