Regulation of neuronal genomic integrity through histone deacetylase cooperativity

Abstract

While the mechanisms preserving genomic integrity are well defined in proliferating cells, corresponding pathways in postmitotic neurons remain poorly understood. In this report, I characterize the functions of two lysine deacetylases, SIRT1 and HDAC1, in the neuronal response to DNA double strand breaks (DSBs). Both SIRT1 and HDAC1 were previously shown to promote neuronal survival in a mouse model of neurodegeneration in which the appearance of DSBs precedes other neurotoxic symptoms. Here I show for the first time the recruitment of both SIRT1 and HDAC1 to sites of DNA DSBs in neurons, where they work cooperatively to coordinate DSB signaling and DNA repair. SIRT1 physically binds HDAC1 and this interaction is strengthened upon DNA damage. I demonstrate that SIRT1 deacetylates HDAC1 at a critical lysine residue, K432, and stimulates its enzymatic activity. Moreover, HDAC1 mutants that mimic a constitutively acetylated state render neurons more susceptible to DNA damaging agents, and pharmacological SIRT1 activators that promote HDAC1 deacetylation also mitigate neuronal loss in a mouse model of neurodegeneration. I propose that the interaction between SIRT1 and HDAC1 constitutes an essential step in the DNA damage response that could be exploited to enhance neuronal survival in various neurodegenerative diseases.