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Science 334 (6055): 525-528

Copyright © 2011 by the American Association for the Advancement of Science

BRCA1 Tumor Suppression Depends on BRCT Phosphoprotein Binding, But Not Its E3 Ligase Activity

Reena Shakya,1,2,* Latarsha J. Reid,1,2,* Colleen R. Reczek,1,3 Francesca Cole,4 Dieter Egli,5 Chyuan-Sheng Lin,2 Dirk G. deRooij,6 Steffen Hirsch,1,2 Kandasamy Ravi,7 James B. Hicks,7 Matthias Szabolcs,2,8 Maria Jasin,4 Richard Baer,1,2,8,{dagger} Thomas Ludwig1,2,8,{dagger}

Abstract: Germline mutations of the breast cancer 1 (BRCA1) gene are a major cause of familial breast and ovarian cancer. The BRCA1 protein displays E3 ubiquitin ligase activity, and this enzymatic function is thought to be required for tumor suppression. To test this hypothesis, we generated mice that express an enzymatically defective Brca1. We found that this mutant Brca1 prevents tumor formation to the same degree as does wild-type Brca1 in three different genetically engineered mouse (GEM) models of cancer. In contrast, a mutation that ablates phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicits tumors in each of the three GEM models. Thus, BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression.

1 Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
2 Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
3 Department of Nutritional and Metabolic Biology, Columbia University, New York, NY 10032, USA.
4 Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
5 New York Stem Cell Foundation (NYSCF), New York, NY 10032, USA.
6 Center for Reproductive Medicine, Amsterdam Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands.
7 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
8 Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: tl54{at}columbia.edu (T.L.); rb670{at}columbia.edu (R.B.)


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