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Sirtuins comprise a family of NAD⁺-dependent protein deacetylases and ADP-ribosyltransferases. Mammalian SIRT1 – a homolog of yeast Sir2, the prototypical member of the sirtuin family – is an important regulator of metabolism, cell differentiation and senescence, stress response, and cancer. As an NAD⁺-dependent enzyme, SIRT1 regulates gene expression programs in response to cellular metabolic status, thereby coordinating metabolic adaptation of the whole organism. Several important mechanisms have emerged for SIRT1-dependent regulation of transcription. First, SIRT1 can modulate chromatin function through direct deacetylation of histones as well as by promoting alterations in the methylation of histones and DNA, leading to the repression of transcription. The latter is accomplished through the recruitment of other nuclear enzymes to chromatin for histone methylation and DNA CpG methylation …