A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

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Item Type:	Article
Title:	A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Creators Name:	Fujita, K., Nakamura, Y., Oka, T., Ito, H., Tamura, T., Tagawa, K., Sasabe, T., Katsuta, A., Motoki, K., Shiwaku, H., Sone, M., Yoshida, C., Katsuno, M., Eishi, Y., Murata, M., Taylor, J.P., Wanker, E.E., Kono, K., Tashiro, S., Sobue, G., La Spada, A.R. and Okazawa, H.
Abstract:	It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.
Keywords:	Adenosine Triphosphatases, Cell Cycle Proteins, Cerebral Cortex, DNA Repair, Double-Stranded DNA Breaks, Endoplasmic Reticulum, Green Fluorescent Proteins, HEK293 Cells, HeLa Cells, Histones, Immunoprecipitation, Inclusion Bodies, Longevity, Motor Neurons, Mutant Proteins, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Phenotype, Protein Binding, Protein Transport, Animals, Drosophila melanogaster, Mice
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	4
Page Range:	1816
Date:	2013
Official Publication:	https://doi.org/10.1038/ncomms2828
PubMed:	View item in PubMed

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