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Sirtuins (Sirts) compose a family of NAD(+)-dependent deacetylases and/or ADP-ribosyltransferases, which have been implicated in aging, metabolism, and tolerance to oxidative stress. Many of the biological processes regulated by Sirts result from the adaptation of complex gene-expression programs to the energetic state of the cell, sensed through NAD(+) levels. To that respect, Sirts, and particularly the founding member of the family Sirt1, have emerged as important regulators of transcription, which they modulate both positively and negatively by targeting histones and transcriptional complex regulatory proteins. This review will focus on recent advances that have started deciphering how mammalian Sirts regulate transcriptional networks and thereby control physiology.