IDENTIFICATION OF POLYGLUTAMINE EXPANDED SCA7-ASSOCIATED PROTEINS

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In eukaryotes, DNA exists in the context of chromatin, in which it is tightly wrapped around histone proteins and consequently highly compacted. This close interaction between DNA and histones presents a fundamental problem for processes such as transcription, replication, and DNA repair in which direct access to the DNA template is required by the proteins that carry out these processes. Many chromatin modifying complexes, such as histone acetyltransferases (HATs) have been shown to regulate chromatin accessibility by transferring different moieties, such as acetyl groups, to the tail regions of histone proteins. Acetylated histones are often associated with transcriptionally active chromatin. The yeast HAT complex SAGA (for Spt-Ada-Gcn5 Acetyltransferase) is a highly conserved complex that has been shown to preferentially acetylate histones H3 and H2B. Another HAT identified in yeast, the SLIK (SAGA-Like) complex, is highly related to SAGA. The two have been shown to have a number of shared components and functions, as well as certain unique proteins. Novel proteins have been identified in both SAGA and SLIK by mass spectrometry, including that encoded by an open reading frame of unknown function. This protein contains domains which are homologous to the human gene SCA7, which encodes a protein responsible for the neurodegenerative disorder, spinocerebellar ataxia type 7. The physiological role of the normal SCA7 protein is unknown. Furthermore, the normal human SCA7 gene, but not the diseased version, compliments loss of the yeast SCA7 gene. However the polyglutamine expanded SCA7 protein (60Q) assembles a SAGA complex, which is unable to acetylate a chromatin template. Silver stain analysis indicates association of at least one putative novel protein in this 60Q complex, which may contribute to disease pathogenesis. The identification of this subunit may have significant implications for the function of the human SCA7 protein in disease pathogenesis.