Chromatin Remodeling Function of BRCA1 and Its Implication in Regulation of DNA Replication
Abstract
The breast cancer susceptibility gene BRCA1 encodes a protein that has been implicated in multiple nuclear functions including transcription and DNA repair. The multifunctional nature of BRCA1 has raised the possibility that the polypeptide may regulate various nuclear processes via a common underlying mechanism such as chromatin remodeling. However, to date no direct evidence exists in mammalian cells for BRCA1-mediated changes in either local- or large-scale chromatin structure. Here we show that targeting BRCA1 to a specific chromosome location in the mammalian genome results in large-scale chromatin decondensation. This unfolding activity is conferred by three independent domains in BRCA1, including the two BRCA1 C-terminus (BRCT) repeats. in addition, we also demonstrate a similar chromatin unfolding activity associated with the trans-activation domains of E2F1 and tumor suppressor p53. However, unlike E2F1 and p53, the BRCT-mediated chromatin unfolding is not accompanied by histone hyperacetylation. Cancer-predisposing mutations of BRCA1 display an allele-specific effect on chromatin unfolding: 5' mutations that result in gross truncation of the protein abolish the chromatin unfolding activity, whereas those in the 3' region of the gene markedly enhance this activity. A novel cofactor of BRCA1 (COBRA1) is recruited to the chromosome site by the first BRCT repeat of BRCA1 and is itself sufficient to induce chromatin unfolding. BRCA1 mutations that enhance chromatin unfolding also increase its affinity for, and recruitment of, COBRA1. These results indicate that reorganization of higher levels of chromatin structure is an important regulated step in BRCA1-mediated nuclear functions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADB282255
Entities
People
- Rong Li
Organizations
- University of Virginia