Cited by 219DNA Repair MechanismsEpigenetics and DNA MethylationHistone Deacetylase Inhibitors Research

HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease

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Pao, Ping-Chieh, Patnaik, Debasis, Watson, L. Ashley, Gao, Fan, Pan, Ling, Wang, Jun, Adaikkan, Chinnakkaruppan, Penney, Jay +10 more·2020·Nature Communications

Abstract

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.

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Authors
Pao, P.-C., Patnaik, D., Watson, L. A., Gao, F., Pan, L., Wang, J., Adaikkan, C., Penney, J., Cam, H. P., Huang, W.-C., Pantano, L., Lee, A., Nott, A., Phan, T. X., Gjoneska, E., Elmsaouri, S., Haggarty, S. J., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Harvard University (US)
  • California Institute of Technology (US)
  • University of California San Diego (US)
  • National Institutes of Health (US)
Corresponding author
Tsai, Li-Huei
Venue
Nature Communications
Published
2020-05-18
Volume
11
Issue
1
Pages
2484-2484
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3025772309
Cited by
216
References
72
Citations by year
2026: 25 · 2025: 45 · 2024: 38 · 2023: 37 · 2022: 41 · 2021: 23 · 2020: 7
FWCI
8.92
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • IslandScholar (University of Prince Edward Island) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG046174)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS102730)
  • Glenn Foundation for Medical Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
HDAC1, OGG1, 8-oxoguanine, oxidative DNA damage repair, brain aging, Alzheimer's disease, DNA glycosylase, transcriptional repression, cognitive impairment, 5xFAD mice, neurodegeneration, DNA damage accumulation
MeSH terms
Acetylation, Aging, Alzheimer Disease, Animals, Astrocytes, Base Sequence, Benzophenones, Brain, Cognition, Cognition Disorders, DNA Damage, Guanine, Memory, Mice, Inbred C57BL, Neurons, Promoter Regions, Genetic, Down-Regulation, Mice, Knockout, Oxidative Stress, DNA Glycosylases, Histone Deacetylase 1, Gene Ontology

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