SIRTUINS 3º part

As well as yeast SIR2, its mammalian homolog SIRT1 was shown to be able to deacetylate histones and preferentially deacetylates lysine (K) residue 9 of histone 3 (H3K9) and lysine 16 of histone 4 (H4K16) in vitro (Imai et al., 2000; Vaquero et al., 2004). SIRT1-deficient mouse embryonic fibroblasts (MEFs) also accumulate hyperacetylated histones, thereby promoting heterochromatin formation and transcription repression (Vaquero et al., 2007; Wang et al., 2008). SIRT1 deletion in MEFs also leads to histone H3K9 hypomethylation (Vaquero et al., 2007). SIRT1 directly binds to the histone methyltransferase Suv39h1 and upregulates its methyltransferase activity by deacetylating lysine residue 266, which resides in the SET domain of Suv39h1. SIRT1 also interacts with linker histone H1b and deacetylates its lysine 26 (H1K26) (Vaquero et al., 2004). In response to oxidative stress, SIRT1 is redistributed and so binds to acetylated histone H1K26, which leads to the repression of various set of genes. Interestingly, the transcriptional repression pattern is similar to that observed in the mouse brain with aging (Oberdoerffer et al., 2008). Thus, it can be speculated that SIRT1 is responsible for aging-dependent global transcriptional changes through chromatin modification.