Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability.
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.
Pontano
Laura L
LL
Department of Cancer Biology, The Abramson Family Cancer Research Institute, 454 BRB II/III, Philadelphia, PA 19104-6140, USA.
Aggarwal
Priya
P
Barbash
Olena
O
Brown
Eric J
EJ
Bassing
Craig H
CH
Diehl
J Alan
JA
D016475:3T3 Cells; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D042822:Genomic Instability; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D016196:S Phase; D025521:Tumor Suppressor Proteins; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex