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

Nature Neuroscience volume 16, pages 1008–1015 (2013)Cite this article

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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.

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Figure 1: SIRT1 is necessary for initial DSB signaling events and DNA repair in neurons.
Figure 2: SIRT1 and HDAC1 interact physically and localize to DSB sites in neurons.
Figure 3: SIRT1 stabilizes HDAC1 at sites of DNA DSBs in neurons.
Figure 4: SIRT1 deacetylates HDAC1 at residue Lys432 and stimulates its enzymatic activity.
Figure 5: Deacetylation of HDAC1 is essential for DSB repair in neurons.
Figure 6: Pharmacological SIRT1 activation can protect neurons against DNA damage in vivo.

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  • 26 July 2013

    In the version of this article initially published online, author Biafra Ahanonu's name was misspelled Ahononu. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

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.

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Author notes

  1. Jun Gao

    Present address: Present address: Model Animal Research Center, Ministry of Education Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing, China.,

  2. Matthew M Dobbin and Ram Madabhushi: These authors contributed equally to this work.

Authors and Affiliations

  1. Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA

    Matthew M Dobbin, Ram Madabhushi, Ling Pan, Jun Gao, Biafra Ahanonu, Ping-Chieh Pao & Li-Huei Tsai

  2. Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA

    Matthew M Dobbin, Ram Madabhushi, Ling Pan, Jun Gao, Biafra Ahanonu, Ping-Chieh Pao & Li-Huei Tsai

  3. Howard Hughes Medical Institute, MIT, Cambridge, Massachusetts, USA

    Matthew M Dobbin, Ram Madabhushi, Ling Pan, Jun Gao, Biafra Ahanonu, Ping-Chieh Pao & Li-Huei Tsai

  4. Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA

    Yue Chen & Yingming Zhao

  5. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Yue Chen & Yingming Zhao

  6. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA

    Dohoon Kim

  7. Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, USA

    Yi Qiu

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Contributions

This study was designed by M.M.D., R.M. and L.-H.T. and was directed and coordinated by L.-H.T. M.M.D. and R.M. planned and performed most of the experiments. L.P. maintained the Sirt1loxP/loxP and Hdac1loxP/loxP mice and, together with B.A., helped with the microirradiation experiments. Y.C. and Y.Z. conducted the mass spectrometry analysis of HDAC1 acetylation. D.K. and J.G. performed some preliminary experiments with CK-p25 mice, and J.G. performed the compound #10 treatment and subsequent analysis of CK-p25 mice. P.-C.P. contributed to statistical analysis and quantification of several experiments, and Y.Q. developed and provided the antibody to acetylated HDAC1 Lys432. R.M., M.M.D. and L.-H.T. wrote the manuscript with critical input from all the authors.

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Correspondence to Li-Huei Tsai.

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Dobbin, M., Madabhushi, R., Pan, L. et al. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci 16, 1008–1015 (2013). https://doi.org/10.1038/nn.3460

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