Analysis BAP-1 as a Ubiquitin Hydrolase in the BRCA1 Pathway
Abstract
The BRCA1 - associated protein ZBRK1 is a member of the KRAB domain-zinc-finger protein (ZFPs) superfamily. The more than 220 KRAB-ZFPs encoded by the human genome function as gene-specific silencers. Silencing requires binding to the co-repressor, KAP-1, that in turn coordinates the activities of large macromolecular complexes that modify chromatin structure. The PHD finger and bromodomain of KAP-1 recruits the NuRD HDAC complex whereas a separate region of KAP-1 binds directly to the chromoshadow domain of the HP1 protein family. Since the HP1 chromodomain can bind to the methylated Lys-9 in histone H3, we looked for this activity in KAP-1 repression complexes. We have recently discovered a novel KAP-1 associated H3, Lys-9 specific histone methyltransferase, SETDB1. The enzymatic activity of SETDB1 increased HP1 binding to histone H3 and CHIP experiments showed co-localization of KAP-1, SETDB1, and HP1 along with increased H3 Lys-9 methylation of chromatin at an endogenous target gene to stably repress expression. KAP-1 is the first example of a co-repressor/scaffold protein that can coordinate the sequential recruitment of HDAC complexes, histone methylase, and the deposition of HP1 at a euchromatic locus to silence gene expression in a manner consistent with epigenetic regulation. These studies define the molecular machinery utilized by ZBRK1 to regulate gene expression, current studies are focused at evaluating the role of KAP-1:SETDB1:HP1 and ZBRK1:BRCA1 regulation of endogenous target genes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADA405424
Entities
People
- David C. Schultz
Organizations
- University of Pennsylvania