Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function.

Abstract:

:The breast and ovarian cancer specific tumor suppressor BRCA1, bound to BARD1, has multiple functions aimed at maintaining genomic stability in the cell. We have shown earlier that the BRCA1/BARD1 E3 ubiquitin ligase activity regulates centrosome-dependent microtubule nucleation. In this study, we tested which domains of BRCA1 and BARD1 were required to control the centrosome function. In the present study, (a) we confirmed that the ubiquitination activity of BRCA1 regulates centrosome number and function in Hs578T breast cancer cells; (b) we observed that both the amino and carboxyl termini of BRCA1 are required for regulation of centrosome function in vitro; (c) an internal domain (770-1,290) is dispensable for centrosome regulation; (d) BARD1 is required for regulation of centrosome function and protein sequences within the terminal 485 amino acids are necessary for activity; and (e) BARD1 is localized at the centrosome throughout the cell cycle. We conclude that the BRCA1-dependent E3 ubiquitin ligase functions to restrain centrosomes in mammary cells, and loss of BRCA1 in the precancerous breast cell leads to centrosomal hypertrophy, a phenotype commonly observed in incipient breast cancer.

journal_name

Cancer Res

journal_title

Cancer research

authors

Sankaran S,Starita LM,Simons AM,Parvin JD

doi

10.1158/0008-5472.CAN-05-4430

subject

Has Abstract

pub_date

2006-04-15 00:00:00

pages

4100-7

issue

8

eissn

0008-5472

issn

1538-7445

pii

66/8/4100

journal_volume

66

pub_type

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