• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity.

The breast and ovarian tumor suppressor BRCA1 constitutes a RING heterodimer E3 ligase with BARD1. BRCA1-associated protein 1 (BAP1) is a ubiquitin COOH-terminal hydrolase that was initially identified as a protein that bound to the RING finger domain of BRCA1. However, how BAP1 contributes to the E3 activity of BRCA1/BARD1 is unclear. Here, we report that BAP1 interacts with BARD1 to inhibit the E3 ligase activity of BRCA1/BARD1. Domains comprised by residues 182-365 of BAP1 interact with the RING finger domain of BARD1, and surface plasmon resonance spectroscopy (BIAcore) analyses showed that BAP1 interferes with the BRCA1/BARD1 association. The perturbation resulted in inhibition of BRCA1 autoubiquitination and NPM1/B23 ubiquitination by BRCA1/BARD1. Although BAP1 was capable of deubiquitinating the polyubiquitin chains mediated by BRCA1/BARD1 in vitro, a catalytically inactive mutant of BAP1, C91S, still inhibited the ubiquitination in vitro and in vivo, implicating a second mechanism of action. Importantly, inhibition of BAP1 expression by short hairpin RNA resulted in hypersensitivity of the cells to ionizing irradiation and in retardation of S-phase progression. Together, these results suggest that BAP1 and BRCA1/BARD1 coordinately regulate ubiquitination during the DNA damage response and the cell cycle.

Pubmed ID: 19117993


  • Nishikawa H
  • Wu W
  • Koike A
  • Kojima R
  • Gomi H
  • Fukuda M
  • Ohta T


Cancer research

Publication Data

January 1, 2009

Associated Grants


Mesh Terms

  • BRCA1 Protein
  • Cell Line, Transformed
  • Down-Regulation
  • HeLa Cells
  • Humans
  • Infrared Rays
  • RNA, Small Interfering
  • S Phase
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Ubiquitin Thiolesterase
  • Ubiquitin-Protein Ligases