Abstract:
:BRCA1 is a breast and ovarian cancer-specific tumor suppressor that seems to be involved in transcription and DNA repair. Here we report that BRCA1 exhibits a bona fide ubiquitin (Ub) protein ligase (E3) activity, and that cancer-predisposing mutations within the BRCA1 RING domain abolish its Ub ligase activity. Furthermore, these mutants are unable to reverse gamma-radiation hypersensitivity of BRCA1-null human breast cancer cells, HCC1937. Additionally, these mutations within the BRCA1 RING domain are not capable of restoring a G(2) + M checkpoint in HCC1937 cells. These results establish a link between Ub protein ligase activity and gamma-radiation protection function of BRCA1, and provide an explanation for why mutations within the BRCA1 RING domain predispose to cancer. Furthermore, we propose that the analysis of the Ub ligase activity of RING-domain mutations identified in patients may constitute an assay to predict predisposition to cancer.
journal_name
Proc Natl Acad Sci U S Aauthors
Ruffner H,Joazeiro CA,Hemmati D,Hunter T,Verma IMdoi
10.1073/pnas.081068398keywords:
subject
Has Abstractpub_date
2001-04-24 00:00:00pages
5134-9issue
9eissn
0027-8424issn
1091-6490pii
98/9/5134journal_volume
98pub_type
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