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Mutant huntingtin impairs Ku70-mediated DNA repair

DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and...

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Autores principales: Enokido, Yasushi, Tamura, Takuya, Ito, Hikaru, Arumughan, Anup, Komuro, Akihiko, Shiwaku, Hiroki, Sone, Masaki, Foulle, Raphaele, Sawada, Hirohide, Ishiguro, Hiroshi, Ono, Tetsuya, Murata, Miho, Kanazawa, Ichiro, Tomilin, Nikolai, Tagawa, Kazuhiko, Wanker, Erich E., Okazawa, Hitoshi
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867301/
https://www.ncbi.nlm.nih.gov/pubmed/20439996
http://dx.doi.org/10.1083/jcb.200905138
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author Enokido, Yasushi
Tamura, Takuya
Ito, Hikaru
Arumughan, Anup
Komuro, Akihiko
Shiwaku, Hiroki
Sone, Masaki
Foulle, Raphaele
Sawada, Hirohide
Ishiguro, Hiroshi
Ono, Tetsuya
Murata, Miho
Kanazawa, Ichiro
Tomilin, Nikolai
Tagawa, Kazuhiko
Wanker, Erich E.
Okazawa, Hitoshi
author_facet Enokido, Yasushi
Tamura, Takuya
Ito, Hikaru
Arumughan, Anup
Komuro, Akihiko
Shiwaku, Hiroki
Sone, Masaki
Foulle, Raphaele
Sawada, Hirohide
Ishiguro, Hiroshi
Ono, Tetsuya
Murata, Miho
Kanazawa, Ichiro
Tomilin, Nikolai
Tagawa, Kazuhiko
Wanker, Erich E.
Okazawa, Hitoshi
author_sort Enokido, Yasushi
collection PubMed
description DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt–expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington’s disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology.
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spelling pubmed-28673012010-11-03 Mutant huntingtin impairs Ku70-mediated DNA repair Enokido, Yasushi Tamura, Takuya Ito, Hikaru Arumughan, Anup Komuro, Akihiko Shiwaku, Hiroki Sone, Masaki Foulle, Raphaele Sawada, Hirohide Ishiguro, Hiroshi Ono, Tetsuya Murata, Miho Kanazawa, Ichiro Tomilin, Nikolai Tagawa, Kazuhiko Wanker, Erich E. Okazawa, Hitoshi J Cell Biol Research Articles DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt–expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington’s disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology. The Rockefeller University Press 2010-05-03 /pmc/articles/PMC2867301/ /pubmed/20439996 http://dx.doi.org/10.1083/jcb.200905138 Text en © 2010 Enokido et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Enokido, Yasushi
Tamura, Takuya
Ito, Hikaru
Arumughan, Anup
Komuro, Akihiko
Shiwaku, Hiroki
Sone, Masaki
Foulle, Raphaele
Sawada, Hirohide
Ishiguro, Hiroshi
Ono, Tetsuya
Murata, Miho
Kanazawa, Ichiro
Tomilin, Nikolai
Tagawa, Kazuhiko
Wanker, Erich E.
Okazawa, Hitoshi
Mutant huntingtin impairs Ku70-mediated DNA repair
title Mutant huntingtin impairs Ku70-mediated DNA repair
title_full Mutant huntingtin impairs Ku70-mediated DNA repair
title_fullStr Mutant huntingtin impairs Ku70-mediated DNA repair
title_full_unstemmed Mutant huntingtin impairs Ku70-mediated DNA repair
title_short Mutant huntingtin impairs Ku70-mediated DNA repair
title_sort mutant huntingtin impairs ku70-mediated dna repair
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867301/
https://www.ncbi.nlm.nih.gov/pubmed/20439996
http://dx.doi.org/10.1083/jcb.200905138
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