SIRT1 limits neuronal fate following DNA damage

DNA damage is a major risk factor for the decline of neuronal functions with age and neurodegenerative diseases. The connection between DNA damage and neurodegeneration is extensively investigated, however, the mechanisms limiting the propagation of damaged DNA from highly replicative neural stem/progenitor cells (NSPCs) to post-mitotic neurons remains largely unknown. Here, we describe that enzymatic activity of the histone deacetylase sirtuin 1 (SIRT1) is important for the homologues recombination-dependent repair of double- stranded DNA breaks induced by etoposide. Furthemore, SIRT1 abolishes neuronal fate of murine NSPCs following induction of DNA damage. Pharmacological inhibition or genetic inactivation of SIRT1 rescues etoposide-mediated inhibition of neuronal differentiation in NSPCs and hippocampal slice cultures and promotes transcription of pro-neuronal genes. Inhibition of Ataxia-telangiectasia mutated (ATM), the central regulator of the DNA damage response, mimics the SIRT-dependent effect of DNA damage on neuronal differentiation, indicating that the ATM/SIRT1 axis inhibits formation of neuronal cells harbouring damaged DNA. These data are consistent with the role of SIRT1 in genome stability, healthy ageing and protection from the development of ageing-associated neurodegenerative diseases.