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Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function

Oncogene volume 28, pages 1843–1852 (2009)Cite this article

Abstract

Germline mutations in two major susceptibility genes, BRCA1 and BRCA2, account for nearly 20% of familial breast cancers. A majority of the remaining genetic factors involved in heritable breast cancer susceptibility are, however, unknown. Recently, a new BRCA1-interacting protein, receptor associated protein 80 (RAP80), was identified. RAP80 plays an important role in BRCA1-mediated DNA damage responses (DDRs) by recruiting BRCA1 to DNA double-strand breaks (DSBs). A comprehensive screening of DNA from affected index cases of 112 BRCA1/BRCA2 mutation-negative Finnish breast cancer families revealed altogether 10 alterations in RAP80, one of which, c.241-243delGAA, resulted in a single glutamic acid deletion at residue 81 in a highly conserved region of ubiquitin interaction motif 1. The resultant delE81 protein product displayed significantly reduced ubiquitin binding and DSB localization. Expression of the RAP80 delE81 allele impaired both BRCA1 and ABRA1 DSB recruitment, thus compromising BRCA1-mediated DDR signaling. Compared with wild-type RAP80, expression of the delE81 allele was associated with a significant increase in cytogenetically detectable chromosomal aberrations, particularly chromatid breaks. Although evidently quite rare, these results suggest that critical constitutional mutations in RAP80 abrogate DDR function and may be involved in genetic predisposition to cancer.

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Acknowledgements

We would like to thank Dr Aki Mustonen, Dr Jaakko Ignatius, Dr Ylermi Soini, Dr Mervi Grip and Dr Arja Jukkola-Vuorinen for their contribution, and nurses Kari Mononen and Outi Kajula for their help in patient contacts and Ms Helmi Konola for technical assistance. We also gratefully acknowledge Dr Junjie Chen for the antibodies to ABRA1, and Dr David Livingston for critical discussion of the manuscript before submission. The Finnish Breast Cancer Group, the Cancer Foundation of Northern Finland, the Orion-Farmos Research Foundation, the Academy of Finland, the Finnish Cancer Society, the Foundation for the Finnish Cancer Institute and the Sigrid Juselius Foundation to RW, the NIH training grant T32-GM-007229 to KAC and the National Cancer Institute K08 award 1K08CA106597-01, the Sidney Kimmel Foundation Scholar Award, the Mary Kay Ash Charitable Foundation Cancer Research Grant and funds from the Abramson Family Cancer Research Institute to RAG financially supported this study.

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  1. J Nikkilä, K A Coleman and D Morrissey: These authors contributed equally to work

Authors and Affiliations

  1. Department of Clinical Genetics and Biocenter Oulu, Laboratory of Cancer Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland

    J Nikkilä, K Pylkäs, H Erkko, S-M Karppinen, A Amelina & R Winqvist

  2. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    K A Coleman, D Morrissey, T E Messick & R A Greenberg

  3. Department of Pathology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    R A Greenberg

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Nikkilä, J., Coleman, K., Morrissey, D. et al. Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function. Oncogene 28, 1843–1852 (2009). https://doi.org/10.1038/onc.2009.33

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