Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration.
The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality.
Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;
Ryan D
RD
Mohan
George
G
Dialynas
Vikki M
VM
Weake
Jianqi
J
Liu
Skylar
S
Martin-Brown
Laurence
L
Florens
Michael P
MP
Washburn
Jerry L
JL
Workman
Susan M
SM
Abmayr
D000595:Amino Acid Sequence; D000818:Animals; D000067719:Ataxin-7; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008136:Longevity / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020836:Protein Structure, Quaternary; D012160:Retina / Q000473:pathology*; D016415:Sequence Alignment; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D006657:Histones; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D064570:Ubiquitin-Specific Proteases
H2B ubiquitination; SAGA complex; spinocerebellar ataxia