Heat-Induced SIRT1-Mediated H4K16ac Deacetylation Impairs Resection and SMARCAD1 Recruitment to Double Strand Breaks

Abstract

Heat stroke deaths are prevalent in tropical regions of the globe. Hyperthermia inhibits DNA double strand break (DSB) repair by homologous recombination (HR) pathway, however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genomic stability and transcription. Heat-induced reduction in H4K16ac were detectable in humans, Drosophila and yeast, suggesting that this is a highly conserved response. We examined the recruitment of several histone deacetylases to chromatin after heat-shock and discovered mainly SIRT1 enrichment to gene-rich regions. Recruitment of SIRT1 upon heat-shock is impacted by SMARCAD1 depletion in an antagonistic manner. Like hyperthermia, SMARCAD1 depletion and a combination of the two, impaired resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a mechanism whereby hyperthermia-induced H4K16ac deacetylation impacts chromatin organization, negatively impacting DSB repair.

Keywords: H4K16ac, SIRT1, MOF, SMARCAD1, heat-shock, DSB repair, replication stress, active replication fork stability, gene rich region