SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons

Matthew M. Dobbin, Ram Madabhushi, Ling Pan, Yue Chen, Dohoon Kim, Jun Gao, Biafra Ahanonu, Ping Chieh Pao, Yi Qiu, Yingming Zhao, Li Huei Tsai

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD + -dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)1008-1015
Number of pages8
JournalNature neuroscience
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Dobbin, M. M., Madabhushi, R., Pan, L., Chen, Y., Kim, D., Gao, J., Ahanonu, B., Pao, P. C., Qiu, Y., Zhao, Y., & Tsai, L. H. (2013). SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nature neuroscience, 16(8), 1008-1015. https://doi.org/10.1038/nn.3460