HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer's disease.
Acetylation
Aging
/ genetics
Alzheimer Disease
/ complications
Animals
Astrocytes
/ drug effects
Base Sequence
Benzophenones
/ pharmacology
Brain
/ pathology
Cognition
/ drug effects
Cognition Disorders
/ complications
DNA Damage
DNA Glycosylases
/ metabolism
Down-Regulation
/ drug effects
Gene Ontology
Guanine
/ analogs & derivatives
Histone Deacetylase 1
/ metabolism
Memory
/ drug effects
Mice, Inbred C57BL
Mice, Knockout
Neurons
/ drug effects
Oxidative Stress
/ drug effects
Promoter Regions, Genetic
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 05 2020
18 05 2020
Historique:
received:
28
03
2019
accepted:
28
04
2020
entrez:
20
5
2020
pubmed:
20
5
2020
medline:
13
8
2020
Statut:
epublish
Résumé
DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.
Identifiants
pubmed: 32424276
doi: 10.1038/s41467-020-16361-y
pii: 10.1038/s41467-020-16361-y
pmc: PMC7235043
doi:
Substances chimiques
Benzophenones
0
exifone
38K9TOD4EG
8-hydroxyguanine
5614-64-2
Guanine
5Z93L87A1R
DNA Glycosylases
EC 3.2.2.-
Ogg1 protein, mouse
EC 3.2.2.-
Hdac1 protein, mouse
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
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
2484Subventions
Organisme : NIA NIH HHS
ID : R01 AG046174
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102730
Pays : United States
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