Human Molecular Genetics Advance Access originally published online on January 10, 2006
Human Molecular Genetics 2006 15(4):599-606; doi:10.1093/hmg/ddi476
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility
1Department of Medical and Molecular Genetics, Kings College London School of Medicine at Guy's, Kings and St Thomas' Hospitals, London, UK, 2Medical Research Council Virology Unit, Glasgow G11 5JR, Scotland, UK, 3Present address, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan and 4Institute for Structural Molecular Biology and School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, UK
* To whom correspondence should be addressed at: Department of Medical and Molecular Genetics, Kings College London School of Medicine at Guy's, Kings and St Thomas' Hospitals, 8th Floor, Guy's Tower, Guy's Hospital, St Thomas' Street, London SE1 9RT, UK. Tel: +44 2071883699/82579; Fax: +44 2071882585; Email: jo.morris{at}genetics.kcl.ac.uk
Received November 1, 2005; Accepted January 4, 2006
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 a family history of disease have not been followed in pedigrees, nor there is 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 the 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Malacrida, S. Agata, M. Callegaro, C. Casella, D. Barana, M. C. Scaini, S. Manoukian, C. Oliani, P. Radice, M. Barile, et al. BRCA1 p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy J. Clin. Oncol., January 1, 2008; 26(1): 26 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sankaran, D. E. Crone, R. E. Palazzo, and J. D. Parvin Aurora-A Kinase Regulates Breast Cancer Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation Cancer Res., December 1, 2007; 67(23): 11186 - 11194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Carvalho, S. M. Marsillac, R. Karchin, S. Manoukian, S. Grist, R. F. Swaby, T. P. Urmenyi, E. Rondinelli, R. Silva, L. Gayol, et al. Determination of Cancer Risk Associated with Germ Line BRCA1 Missense Variants by Functional Analysis Cancer Res., February 15, 2007; 67(4): 1494 - 1501. [Abstract] [Full Text] [PDF]
|
|