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

Author

Listed:
  • Ping-Chieh Pao

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Debasis Patnaik

    (Massachusetts General Hospital and Harvard Medical School)

  • L. Ashley Watson

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Fan Gao

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Caltech Bioinformatics Resource Center at Beckman Institute of Caltech)

  • Ling Pan

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Jun Wang

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Chinnakkaruppan Adaikkan

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Jay Penney

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Hugh P. Cam

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Wen-Chin Huang

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Lorena Pantano

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Audrey Lee

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Alexi Nott

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    University of California, San Diego)

  • Trongha X. Phan

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Elizabeta Gjoneska

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    National Institutes of Health)

  • Sara Elmsaouri

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Stephen J. Haggarty

    (Massachusetts General Hospital and Harvard Medical School)

  • Li-Huei Tsai

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • Ping-Chieh Pao & Debasis Patnaik & L. Ashley Watson & Fan Gao & Ling Pan & Jun Wang & Chinnakkaruppan Adaikkan & Jay Penney & Hugh P. Cam & Wen-Chin Huang & Lorena Pantano & Audrey Lee & Alexi Nott & , 2020. "HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16361-y
    DOI: 10.1038/s41467-020-16361-y
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    Cited by:

    1. Tharick A. Pascoal & Mira Chamoun & Elad Lax & Hsiao-Ying Wey & Monica Shin & Kok Pin Ng & Min Su Kang & Sulantha Mathotaarachchi & Andrea L. Benedet & Joseph Therriault & Firoza Z. Lussier & Frederic, 2022. "[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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