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A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers

Nature volume 474, pages 230–234 (2011)Cite this article

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Abstract

Cyclin D1 is a component of the core cell cycle machinery1. Abnormally high levels of cyclin D1 are detected in many human cancer types2. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process3. We found that cyclin D1 directly binds RAD51, and that cyclin D1–RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation4,5. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.

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Figure 1: Analyses of cyclin D1 interactors identified in human cancers.
Figure 2: Impaired DNA repair upon reduction of cyclin D1 levels.
Figure 3: Functional interaction between cyclin D1 and RAD51.
Figure 4: Increased radiation-sensitivity of tumours with reduced cyclin D1 levels.

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References

  1. Sherr, C. J. & Roberts, J. M. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 18, 2699–2711 (2004)

    Article  CAS  Google Scholar 

  2. Deshpande, A., Sicinski, P. & Hinds, P. W. Cyclins and cdks in development and cancer: a perspective. Oncogene 24, 2909–2915 (2005)

    Article  CAS  Google Scholar 

  3. Baumann, P. & West, S. C. Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem. Sci. 23, 247–251 (1998)

    Article  CAS  Google Scholar 

  4. Bates, S. et al. Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene 9, 1633–1640 (1994)

    CAS  PubMed  Google Scholar 

  5. Lukas, J. et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506 (1995)

    Article  ADS  CAS  Google Scholar 

  6. Ek, S., Ortega, E. & Borrebaeck, C. A. K. Transcriptional profiling and assessment of cell lines as in vitro models for mantle cell lymphoma. Leuk. Res. 29, 205–213 (2005)

    Article  CAS  Google Scholar 

  7. Lin, D. I. et al. Phosphorylation-dependent ubiquitination of cyclin D1 by the SCFEBX4-αB crystallin complex. Mol. Cell 24, 355–366 (2006)

    Article  CAS  Google Scholar 

  8. Hosokawa, Y. & Arnold, A. Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: analysis of allele-specific expression. Genes Chromosom. Cancer 22, 66–71 (1998)

    Article  CAS  Google Scholar 

  9. Bartkova, J. et al. Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res. 55, 949–956 (1995)

    CAS  PubMed  Google Scholar 

  10. Nakatani, Y. & Ogryzko, V. Immunoaffinity purification of mammalian protein complexes. Methods Enzymol. 370, 430–444 (2003)

    Article  CAS  Google Scholar 

  11. Kozar, K. et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118, 477–491 (2004)

    Article  CAS  Google Scholar 

  12. Toogood, P. L. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388–2406 (2005)

    Article  CAS  Google Scholar 

  13. Hinds, P. W., Dowdy, S. F., Eaton, E. N., Arnold, A. & Weinberg, R. A. Function of a human cyclin gene as an oncogene. Proc. Natl Acad. Sci. USA 91, 709–713 (1994)

    Article  ADS  CAS  Google Scholar 

  14. Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P. & Hinds, P. W. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9, 13–22 (2006)

    Article  CAS  Google Scholar 

  15. Ostling, O. & Johanson, K. J. Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem. Biophys. Res. Commun. 123, 291–298 (1984)

    Article  CAS  Google Scholar 

  16. Baumann, P., Benson, F. E. & West, S. C. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro . Cell 87, 757–766 (1996)

    Article  CAS  Google Scholar 

  17. Pierce, A. J., Johnson, R. D., Thompson, L. H. & Jasin, M. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 13, 2633–2638 (1999)

    Article  CAS  Google Scholar 

  18. Lord, C. J. & Ashworth, A. Targeted therapy for cancer using PARP inhibitors. Curr. Opin. Pharmacol. 8, 363–369 (2008)

    Article  CAS  Google Scholar 

  19. Agami, R. & Bernards, R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102, 55–66 (2000)

    Article  CAS  Google Scholar 

  20. Pontano, L. L. et al. Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Mol. Cell. Biol. 28, 7245–7258 (2008)

    Article  CAS  Google Scholar 

  21. Coco Martin, J. M., Balkenende, A., Verschoor, T., Lallemand, F. & Michalides, R. Cyclin D1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line. Cancer Res. 59, 1134–1140 (1999)

    CAS  PubMed  Google Scholar 

  22. Sugawara, N., Wang, X. & Haber, J. E. In vivo roles of Rad52, Rad54, and Rad55 proteins in Rad51-mediated recombination. Mol. Cell 12, 209–219 (2003)

    Article  CAS  Google Scholar 

  23. Wolner, B., van Komen, S., Sung, P. & Peterson, C. L. Recruitment of the recombinational repair machinery to a DNA double-strand break in yeast. Mol. Cell 12, 221–232 (2003)

    Article  CAS  Google Scholar 

  24. Rodrigue, A. et al. Interplay between human DNA repair proteins at a unique double-strand break in vivo . EMBO J. 25, 222–231 (2006)

    Article  CAS  Google Scholar 

  25. West, S. C. Molecular views of recombination proteins and their control. Nature Rev. Mol. Cell Biol. 4, 435–445 (2003)

    Article  CAS  Google Scholar 

  26. Lee, M., Daniels, M. J. & Venkitaraman, A. R. Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression. Oncogene 23, 865–872 (2004)

    Article  CAS  Google Scholar 

  27. Li, Z. et al. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 70, 8802–8811 (2010)

    Article  CAS  Google Scholar 

  28. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010)

    Article  ADS  CAS  Google Scholar 

  29. Bienvenu, F. et al. Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463, 374–378 (2010)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the Sicinski lab for help and advice, N. Li for help with initial experiments, S Panyim and Y. Geng for discussions and reading the manuscript, P. Nakatani for pOZ-FH-N construct, M. Jasin for DR-GFP system, D. Bulavin and E. Appella for anti-phospho-CDC25A antibodies, A. Smogorzewska for anti-FANCI antibody, A. Venkitaraman and M. Lee for GST–BRCA2 fragments, and DFCI Confocal and Light Microscopy Core Facility for assisting with confocal microscopy. This work was supported by R01 CA083688, P01 CA080111 and P01 CA109901 grants from NIH (to P.S.). S.J. is supported by The Thailand Research Fund MRG5280248, W.M. by Foundation for Polish Science, Y.E.W. through the CCCB and the Dana-Farber Strategic Plan Initiative, A.B.C. and T.A.K. by Project Z01 ES065089 (to T.A.K.) from the Division of Intramural Research of the NIH, NIEHS.

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Author notes

  1. Joshua E. Elias & Frederic Bienvenu

    Present address: Present addresses: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA (J.E.E.); Institute of Functional Genomics, UMR 5203 CNRS – U 661 INSERM – Université de Montpellier, 34094 Montpellier, France (F.B.).,

  2. Yiduo Hu and Wojciech Michowski: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, and Department of Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Siwanon Jirawatnotai, Yiduo Hu, Wojciech Michowski, Lisa Becks, Frederic Bienvenu, Agnieszka Zagozdzon, Tanja van Harn, David M. Livingston & Piotr Sicinski

  2. Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Prathom, 73170 Thailand ,

    Siwanon Jirawatnotai

  3. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joshua E. Elias, Tapasree Goswami & Steven P. Gygi

  4. Department of Pharmacology, Massachusetts College of Pharmacy and Health Sciences, Boston, 02115, Massachusetts, USA

    Lisa Becks

  5. Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, 02215, Massachusetts, USA

    Yaoyu E. Wang, Mick Correll & John Quackenbush

  6. Department of Health and Human Services, Laboratory of Molecular Genetics and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, North Carolina, USA

    Alan B. Clark & Thomas A. Kunkel

  7. Department of Radiation Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, USA

    Bing Xia

  8. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, 02215, Massachusetts, USA

    John Quackenbush

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  1. Siwanon Jirawatnotai
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Contributions

S.J. and P.S. designed the study, analysed the data and wrote the manuscript. S.J. performed most of the experiments with help from collaborators. Y.H. and D.M.L. contributed to DNA repair analyses. W.M. contributed in vitro protein binding analyses. J.E.E. and T.G. performed mass spectrometry; J.E.E. analysed mass spec data with S.P.G. L.B., F.B., A.Z., T.v.H helped with experiments. Y.E.W. M.C. and J.Q. performed computational analyses of interactors. A.B.C. and T.A.K. contributed DNA mismatch repair analyses. B.X. helped with BRCA2 analyses.

Corresponding author

Correspondence to Piotr Sicinski.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-28 with legends. (PDF 3085 kb)

Supplementary Information

This file contains Supplementary Methods and additional references. (PDF 972 kb)

Supplementary Table 1

This table contains a list of peptides identified in five human cancer cell lines. (XLS 7218 kb)

Supplementary Table 2

This table contains a list of proteins identified in five human cancer cell lines. (XLS 1191 kb)

Supplementary Table 3

This table contains a list of proteins identified in five human cancer cell lines. (XLS 155 kb)

Supplementary Table 4

This table contains a list of proteins identified in five human cancer cell lines. (XLS 60 kb)

Supplementary Table 5

This table contains a summary of proteomic data for proteins mentioned in the text. (XLS 64 kb)

Supplementary Table 6

This table contains the molecular function biological process analyses of cyclin D1 interacting proteins. (XLS 184 kb)

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Jirawatnotai, S., Hu, Y., Michowski, W. et al. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474, 230–234 (2011). https://doi.org/10.1038/nature10155

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