McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR, Grant PA.
Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity.
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8478-82.
Please login to recommend the paper.
Make a Comment
McMahon et al. present convincing evidence of a connection between a neurodegenerative, trinucleotide expansion repeat disorder, spinocerebellar ataxia 7, and chromatin-dependent gene activation. Sgf73 is a key component of the SAGA and SLIK transcriptional coactivator complexes in yeast, which contain histone acetyltransferase activity. This protein is a homologue of the human protein ataxin 7 (Sca7), the culprit in spinocerebellar ataxia 7.
The human gene contains a trinucleotide repeat, expansion of which renders the protein product inactive in the assembly of a functional SAGA or SLIK complex in yeast. This has profound implications for the expression of a wide array of genes. SAGA is the functional equivalent of transcriptional coactivator complexes in humans, and contains the Gcn5 histone acetylase, homologues of which are found in the human complex. It has been shown in our laboratory that SLIK plays an important role in determining lifespan in yeast by reading the metabolic state of mitochondria and compensating for declining mitochondrial function by activating metabolic genes.
The Rtg2 protein in SLIK is key in this regard. When it is not engaged in this activity, it is free to suppress genome instability, and it has been found to prevent the expansion of trinucleotide repeats. Thus, Rtg2 plays a pivotal role, allowing the cell to ultimately respond to metabolic dysfunction but at the expense of genome stability. The McMahon et al. results show a similar role for Sfg73/Sca7. However, the direction of the effect is such that genome instability leads to a loss in the ability to compensate for metabolic dysfunction. All of this is tied together by the transcriptional coactivator SLIK. Here we find yet again a self-accelerating downward spiral of functional decline during aging.
To make a comment you must login or register.