Sir2: An NAD-dependent Histone Deacetylase That Connects Chromatin Silencing, Metabolism, and Aging

Excerpt

Aging is a biological process that shows deleterious,progressive, intrinsic, and universal changes in an organism over time (Strehler 1982). These destructive changeseventually produce an exponential increase of mortalityrate (Gompertz 1825), which can be widely observed in avariety of organisms including the budding yeast Saccharomyces cerevisiae (Sinclair et al. 1998). Different typesof damage, especially oxidative damage, and variousforms of genomic instability have been suggested to beinvolved in the aging process (Johnson et al. 1999). In thecase of budding yeast, longevity is measured by the number of daughter cells that a mother cell can produce (Mortimer and Johnston 1959). The stability of ribosomalDNA (rDNA) repeats is crucial to determine thelongevity of the yeast mother cell (Sinclair and Guarente1997). The rDNA region consists of 100–200 tandemcopies of an approximately 9.0-kb rDNA unit and therefore presents a large target for homologous recombination. Playing a major part in the regulation of the frequency of recombination at this locus is the yeastsilencing protein Sir2 (Gottlieb and Esposito 1989),which is also a limiting component for longevity (Kaeberlein et al. 1999). Deletion of SIR2 shortens life span toabout one half of wild type, and an extra copy of SIR2 significantly extends life span. Sir2 is one of the principalregulators of transcriptional silencing in yeast, along withSir3 and Sir4 at telomeres and silent mating-type (HM)loci (Rine and Herskowitz 1987; Gottschling et al. 1990)and Net1 and Cdc14 at the rDNA locus (Bryk et al. 1997;Smith and Boeke 1997; Straight et al. 1999). The extension of life span by Sir2 likely results from an increasedsilencing in the rDNA that reduces recombination. This,in turn, reduces the production of extrachromosomalrDNA circles (ERCs), a known cause of senescence inaging mother cells (Sinclair and Guarente 1997). Sir2proteins are highly conserved in evolution, from bacteriato humans (Brachmann et al. 1995), suggesting that theseproteins may also mediate silencing in higher eukaryotesand raising the possibility that they are involved in theregulation of aging in a similar fashion. A novel biochemical activity of Sir2, nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, was discovered recently (Imai et al. 2000). This activity isessential for Sir2 functions in vivo, including silencing,suppression of rDNA recombination, and promotion ofyeast longevity, and is highly conserved between yeastand mouse. The extraordinary requirement of NAD in adeacetylation reaction opens an intriguing possibility thatSir2 can function as sensors of the energy status of cells,converting the energy level represented by availableNAD to chromatin silencing. In this paper, we summarizeour recent studies of this Sir2 enzymatic activity and discuss implications of the function of Sir2 for the epigeneticregulation of aging...