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

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, Trongha X. Phan, Elizabeta Gjoneska, Sara Elmsaouri, Stephen J. Haggarty and Li-Huei Tsai ()
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Ping-Chieh Pao: Massachusetts Institute of Technology
Debasis Patnaik: Massachusetts General Hospital and Harvard Medical School
L. Ashley Watson: Massachusetts Institute of Technology
Fan Gao: Massachusetts Institute of Technology
Ling Pan: Massachusetts Institute of Technology
Jun Wang: Massachusetts Institute of Technology
Chinnakkaruppan Adaikkan: Massachusetts Institute of Technology
Jay Penney: Massachusetts Institute of Technology
Hugh P. Cam: Massachusetts Institute of Technology
Wen-Chin Huang: Massachusetts Institute of Technology
Lorena Pantano: Massachusetts Institute of Technology
Audrey Lee: Massachusetts Institute of Technology
Alexi Nott: Massachusetts Institute of Technology
Trongha X. Phan: Massachusetts Institute of Technology
Elizabeta Gjoneska: Massachusetts Institute of Technology
Sara Elmsaouri: Massachusetts Institute of Technology
Stephen J. Haggarty: Massachusetts General Hospital and Harvard Medical School
Li-Huei Tsai: Massachusetts Institute of Technology

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16361-y

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