Mammalian sirtuins have emerged in recent years as critical modulators of multiple biological processes, regulating cellular metabolism, DNA repair, gene expression, and mitochondrial biology. As such, they evolved to play key roles in organismal homeostasis, and defects in these proteins have been linked to a plethora of diseases, including cancer, neurodegeneration, and aging. In this review, we describe the multiple roles of SIRT6, a chromatin deacylase with unique and important functions in maintaining cellular homeostasis. We attempt to provide a framework for such different functions, for the ability of SIRT6 to interconnect chromatin dynamics with metabolism and DNA repair, and the open questions the field will face in the future, particularly in the context of putative therapeutic opportunities.
Highlights d The histone deacetylase SIRT6 binds to Pol II and promotes transcriptional pausing d SIRT6 retains NELF by deacetylating intragenically H3K9 and H3K56 d Removal of SIRT6 from chromatin increases K9/K56 acetylation d Recruitment of elongation factors promotes transcriptional elongation of SIRT6 targets
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