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Molecular and Cellular Biology, December 2008, p. 7245-7258, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01085-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Laura L. Pontano,1,2 Priya Aggarwal,1 Olena Barbash,1 Eric J. Brown,1,2 Craig H. Bassing,1,3,4 and J. Alan Diehl1,2*

The Abramson Family Cancer Research Institute,1 Department of Cancer Biology,2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,3 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 191044

Received 10 July 2008/ Returned for modification 28 July 2008/ Accepted 14 September 2008

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-{alpha}Bcrystallin. 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.

* Corresponding author. Mailing address: The Abramson Family Cancer Research Institute, Department of Cancer Biology, 454 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6140. Phone: (215) 746-6389. Fax: (215) 746-5511. E-mail: adiehl{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 22 September 2008.

Molecular and Cellular Biology, December 2008, p. 7245-7258, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01085-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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