Accession Number:

ADA467787

Title:

Deciphering the Molecular Mechanisms of Breast Cancer

Descriptive Note:

Final rept.

Corporate Author:

PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST

Personal Author(s):

Report Date:

2005-03-01

Pagination or Media Count:

34.0

Abstract:

We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant foursubunit complex containing BRCA1BARD1BRCC45BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs siRNAs resulted in increased sensitivity to ionizing radiation and defects in G2M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE