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Human Molecular Genetics Advance Access published online on January 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi476
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 1, 2005
Revised January 4, 2006
Accepted January 4, 2006

Article

Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility

Joanna R Morris 1 *, Laurent Pangon 1, Chris Boutell 2, Toyomasa Katagiri 3, Nicholas H. Keep 4, and Ellen Solomon 1

1 Kings College London School of Medicine at Guy's, Kings & St. Thomas' Hospitals, Dept. Medical and Molecular Genetics, 8th floor Guy's Tower, Guy's Hospital, St. Thomas' Street, London SE1 9RT, UK
2 Medical Research Council Virology Unit, Glasgow G11 5JR, Scotland, UK
3 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
4 Institute for Structural Molecular Biology and School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, UK

* To whom correspondence should be addressed.
Joanna R Morris, E-mail: jo.morris{at}genetics.kcl.ac.uk


  Abstract

The N-terminus of the Breast Cancer-1 predisposition protein (BRCA1) associates with the BRCA1-associated RING domain-1 protein (BARD1) to form a heterodimer which exhibits ubiquitin ligase activity that is abrogated by known cancer-associated BRCA1 missense mutations. The majority of missense substitutions identified in patients with a personal or family history of disease have not been followed in pedigrees, nor is there a functional understanding of their impact. We have examined, by extensive missense substitution, the interaction of BRCA1 with components that contribute to its ubiquitin ligase activity, BARD1 and the E2 ubiquitin-conjugating enzyme UbcH5a. Selection from a randomly generated library of BRCA1 missense mutations for variants that inhibit the interaction with these components identified substitutions in residues found altered in patient DNA, indicating a correlation between loss of component binding and propensity to disease development. We further show that the BRCA1:E2 interaction is sensitive to substitutions in all structural elements of the BRCA1 N-terminus, whereas the BARD1 interaction is sensitive to a subset of BRCA1 substitutions, which also inhibit E2 binding. Patient variants that inhibit the BRCA1:E2 interaction show loss of ubiquitin ligase activity and correlate with disease susceptibility and theoretical predictions of pathogenicity. These data link loss of ubiquitin ligase activity, through loss of E2 binding, to the majority of non-polymorphic patient variants described within the N-terminus of BRCA1 and illustrate the likely significant role of BRCA1 ubiquitin ligase activity in tumour suppression.


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