A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers
Open accessAbstract
Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. 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 process. 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 proliferation. 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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Various noncanonical CDK-dependent and/or CDK-independent roles for nuclear cyclin D1 have been reported, for example, in transcription and DNA double-strand break repair.
“various noncanonical CDK-dependent and/or CDK-independent roles for nuclear cyclin D1 have been reported, for example, in transcription and DNA double-strand break repair (47, 48).”
From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [48]
The paper’s Abstract (page unavailable in our copy) reports that cyclin D1 helps recruit RAD51 to DNA damage sites and supports homologous-recombination repair. It also suggests this repair function may be CDK-independent. The passages do not establish a role for cyclin D1 in transcription, so this source supports the repair example but not the full sentence. (LLM, conf=0.84)
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References 29 · Cited by 333
- Authors
- Jirawatnotai, S., Hu, Y., Michowski, W., Elias, J. E., Becks, L., Bienvenu, F., Zagozdzon, A., Goswami, T., Wang, Y. E., Clark, A. B., Kunkel, T. A., van Harn, T., Xia, B., Correll, M., Quackenbush, J., Livingston, D. M., Gygi, S. P., & Sicinski, P.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- National Institutes of Health (US)
- Rutgers Cancer Institute (US)
- ORCID
- Venue
- Nature
- Published
- 2011-06
- Volume
- 474
- Issue
- 7350
- Pages
- 230-234
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3134411
- OpenAlex
- W2030800943
- Cited by
- 333
- References
- 29
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 26 · 2020: 27 · 2019: 22 · 2018: 23 · 2017: 22 · 2016: 31 · 2015: 28 · 2014: 24 · 2013: 36 · 2012: 32
- FWCI
- 13.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Dana-Farber Cancer Institute
- National Institutes of Health
- National Cancer Institute (R01CA138804, P01CA080111, P01CA109901, R01CA083688)
- National Institute of Allergy and Infectious Diseases (P30AI060354)
- National Institute of Environmental Health Sciences (Z01ES065089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- cyclin D1, DNA repair, homologous recombination, RAD51, BRCA2, retinoblastoma protein, radiosensitivity, protein-protein interaction network
- MeSH terms
- Animals, DNA Damage, DNA Repair, HeLa Cells, Humans, Neoplasms, Protein Binding, Radiation, Ionizing, Recombination, Genetic, Retinoblastoma Protein, Cyclin D1, Comet Assay, Protein Interaction Mapping, Cell Line, Tumor, Rad51 Recombinase, Mice
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