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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Amino Acid Sequence
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / physiology*
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Cell Line
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Cerebral Cortex / cytology
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Comet Assay
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DNA Breaks, Double-Stranded*
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DNA End-Joining Repair / physiology*
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DNA-Binding Proteins / physiology*
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Enzyme Activation / drug effects
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Etoposide / pharmacology
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Genetic Vectors
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Genomic Instability*
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HEK293 Cells
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Hippocampus / cytology
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Histone Deacetylase 1 / genetics
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Histone Deacetylase 1 / immunology
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Histone Deacetylase 1 / physiology*
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Humans
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Neurons / metabolism*
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Phosphorylation
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Protein Interaction Mapping
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / physiology*
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RNA Interference
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Sirtuin 1 / antagonists & inhibitors
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Sirtuin 1 / genetics
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Sirtuin 1 / physiology*
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Tumor Suppressor Proteins / physiology*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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Etoposide
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Sirt1 protein, mouse
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Sirtuin 1
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Hdac1 protein, mouse
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Histone Deacetylase 1