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 language | English (US) |
|---|---|
| Pages (from-to) | 1008-1015 |
| Number of pages | 8 |
| Journal | Nature neuroscience |
| Volume | 16 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2013 |
Bibliographical note
Funding Information:We thank F.W. Alt (Harvard Medical School) and E.N. Olson (University of Texas Southwestern Medical Center) for providing the Sirt1loxP/loxP and Hdac1loxP/loxP mice, respectively; R. Huganir (Johns Hopkins University) for providing the lentiviral Cre constructs; V. Suri, J. Ellis and G. Vlasuk (Sirtris) for providing compound #10 and, together with J. Gräff, for critical comments on the manuscript; M. Kastan (St. Jude’s Medical Research Hospital) for gifting the I-PpoI-ER construct; and V. Gorbunova (University of Rochester) for providing the NHEJ constructs. This work was supported by funding from US National Institutes of Health (NIH) PO1 grant AG27916, the Howard Hughes Medical Institute, the Neurodegeneration Consortium and the Glenn award for research in biological mechanisms of aging to L.-H.T., NIH grant R01 HL095674 to Y.Q. and NIH grant U54 RR020389 to Y.Z. M.M.D. was supported by NIH training grants T32 GM007484 and T32 MH081728.