Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Molecular and Cellular Biology
Xianjiang LanSharon Y R Dent

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a debilitating neurodegenerative disease caused by expansion of a polyglutamine [poly(Q)] tract in ATXN7, a subunit of the deubiquitinase (DUB) module (DUBm) in the SAGA complex. The effects of ATXN7-poly(Q) on DUB activity are not known. To address this important question, we reconstituted the DUBm in vitro with either wild-type ATXN7 or a pathogenic form, ATXN7-92Q NT, with 92 Q residues at the N terminus (NT). We found that both forms of ATXN7 greatly enhance DUB activity but that ATXN7-92Q NT is largely insoluble unless it is incorporated into the DUBm. Cooverexpression of DUBm components in human astrocytes also promoted the solubility of ATXN7-92Q, inhibiting its aggregation into nuclear inclusions that sequester DUBm components, leading to global increases in ubiquitinated H2B (H2Bub) levels. Global H2Bub levels were also increased in the cerebellums of mice in a SCA7 mouse model. Our findings indicate that although ATXN7 poly(Q) expansions do not change the enzymatic activity of the DUBm, they likely contribute to SCA7 by initiating aggregates that sequester the DUBm away from its substrates.

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Citations

Jun 3, 2017·Nucleic Acids Research·Helen J CurtisMiguel A Varela
Oct 30, 2016·Molecular and Cellular Biology·Wenqian LiSharon Y R Dent
Sep 1, 2017·Nature Reviews. Neuroscience·Henry L PaulsonHarry T Orr
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Aug 23, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Anna Niewiadomska-Cimicka, Yvon Trottier
Apr 9, 2016·Oncotarget·Johanna Melo-CardenasDeyu Fang
Jul 4, 2020·Experimental & Molecular Medicine·Youngseo CheonDaeyoup Lee
Jun 26, 2020·Frontiers in Neuroscience·Anna Niewiadomska-CimickaYvon Trottier
Sep 11, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Dayanne V Cornelio-ParraRyan D Mohan
Jul 28, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Carme Nuño-Cabanes, Susana Rodríguez-Navarro
Dec 19, 2020·Molecular and Cellular Neurosciences·Frida NissAnna-Lena Ström
Jun 12, 2021·Epigenetics & Chromatin·Ying-Jiun C Chen, Sharon Y R Dent

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