Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7.
ChIP-seq
DNA damage
ataxin-7
cerebellum
epigenetic dysregulation
neurodegeneration
polyglutamine
repair
spinocerebellar ataxia
translocation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
30 11 2021
30 11 2021
Historique:
received:
07
01
2021
revised:
11
10
2021
accepted:
05
11
2021
entrez:
1
12
2021
pubmed:
2
12
2021
medline:
16
2
2022
Statut:
ppublish
Résumé
A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.
Identifiants
pubmed: 34852229
pii: S2211-1247(21)01548-5
doi: 10.1016/j.celrep.2021.110062
pmc: PMC8710427
mid: NIHMS1763210
pii:
doi:
Substances chimiques
Ataxin-7
0
Histones
0
Peptides
0
polyglutamine
26700-71-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110062Subventions
Organisme : NCI NIH HHS
ID : K99 CA207729
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136627
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY014061
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG033082
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS122140
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declarations of interests The authors declare no competing interests.
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