Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity.
Histone acetyltransferases have been shown to participate in many essential cellular processes, particularly those associated with activation of transcription. SAGA (Spt-Ada-Gcn5 acetyltransferase) and SLIK (SAGA-like) are two highly homologous multisubunit histone acetyltransferase complexes that were originally identified in the yeast Saccharomyces cerevisiae. Here, we identify the protein Sgf73/Sca7 as a component of SAGA and SLIK, and a homologue of the human SCA7-encoded protein ataxin-7, which, in its polyglutamine expanded pathological form, is responsible for the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Our findings indicate that yeast Sca7 is necessary for the integrity and function of both SAGA and SLIK, and that the human ataxin-7 is able to compliment the loss of Sca7 in yeast. A polyglutamine-expanded version of ataxin-7 assembles a SAGA complex that is depleted of critical proteins that regulate the ability of SAGA to acetylate nucleosomes. These observations have significant implications for the function of the human Sca7 protein in disease pathogenesis.
McMahon
Stacey J
SJ
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Pray-Grant
Marilyn G
MG
Schieltz
David
D
Yates
John R
JR
Grant
Patrick A
PA
D000123:Acetyltransferases / Q000235:genetics*; D000595:Amino Acid Sequence; D000067719:Ataxin-7; D015153:Blotting, Western; D051548:Histone Acetyltransferases; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D016415:Sequence Alignment; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D015003:Yeasts / Q000201:enzymology / Q000235:genetics*; D001616:beta-Galactosidase
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C515833:Sgf73 protein, S cerevisiae; D001616:beta-Galactosidase