BRCA1, Everything But the RING?

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Science  28 Oct 2011:
Vol. 334, Issue 6055, pp. 459-460
DOI: 10.1126/science.1214057

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Since its discovery in 1994, familial breast and ovarian cancer susceptibility gene BRCA1 (breast cancer early onset gene 1) has been routinely sequenced in women with family histories for either malignancy (1). Genetic alterations are reported in a public database (, providing a wealth of information on pathogenic mutations in the BRCA1 gene. Mutations found in either the BRCA1 amino or carboxyl terminus confer highly penetrant breast and ovarian cancer risk, suggesting that each domain within the BRCA1 protein plays an essential role in BRCA1-dependent DNA repair (2, 3), thereby limiting cancer susceptibility. On page 525 of this issue, Shakya et al. (4) put this assumption to the test, using elegant in vivo models to show that phosphoprotein binding by the BRCA1 carboxyl-terminal domain is critical for DNA repair and tumor suppression, whereas E3 ligase activity at the amino terminus is not.