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BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation

Oncogene volume 32, pages 5005–5016 (2013)Cite this article

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Abstract

The BRCA1 tumor suppressor protein heterodimerizes with its partner protein, BARD1, via the RING domain present in both proteins. The heterodimer contains an E3 ubiquitin ligase activity and participates in multiple cellular functions such as cell cycle control, DNA repair and regulation of gene transcription, collectively aimed at maintaining genomic stability and tumor suppression. Yet, the precise role of BRCA1 E3 ligase in these cellular functions is poorly understood. We present data showing that BRCA1 ubiquitinates G2/M cell cycle proteins, cyclin B and Cdc25C, leading to their accelerated degradation via a mechanism that is independent of APC/C. BRCA1-dependent degradation of cyclin B and Cdc25C is reversed by proteasome inhibitors and is enhanced following DNA damage, which may represent a possible mechanism to prevent cyclin B and Cdc25C accumulation, a requirement for mitotic entry. Our data provide mechanistic insight into how BRCA1 E3 ligase activity regulates the G2/M cell cycle checkpoint and, thus, contributes to maintenance of genomic stability.

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Acknowledgements

We thank Drs B Henderson, J Pines, R Agami, E Rosen and M Brandeis for providing plasmids and Dr L Brody for reagents. We thank the microscopy unit in Bar-Ilan University for assistance with immunofluorescence studies and Dr I Goldstein and the flow cytometry unit at the Sheba medical center for assistance with fluorescence-activated cell sorting analysis. We thank Allison Hall for technical assistance. We thank Drs Eliot Rosen, Claire Pollack, Michael Brandeis and Gad Lavie for stimulating discussions and critical reading of the manuscript. This study was supported by a Research Career Development Award from the Israel Cancer Research Fund (to RIY) and by the funding from the Health Ministry (to RIY and MZP), the Israeli Cancer Association (RIY) and funds from Georgetown University, SNHS to RIY.

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Author notes

  1. S Shabbeer and D Omer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Science, SNHS, Georgetown University Medical Center, Washington, DC, USA

    S Shabbeer, A Alpaugh, A Pietraszkiewicz & R I Yarden

  2. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    S Shabbeer & R I Yarden

  3. Department of Surgical Oncology, Laboratory of Genomic Applications, Sheba Medical Center, Tel-Hashomer, Israel

    D Omer, D Berneman, O Weitzman, S Metsuyanim, M Z Papa & R I Yarden

  4. Laraine and Alan A. Fischer Laboratory for Biological Mass Spectrometry, Weizmann Institute of Science, Rehovot, Israel

    A Shainskaya

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Shabbeer, S., Omer, D., Berneman, D. et al. BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation. Oncogene 32, 5005–5016 (2013). https://doi.org/10.1038/onc.2012.522

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