Deciphering NAD-Dependent Deacetylases

each region through immunofluorescence, cross-linking Pacific Hall 0347 and chromatin immunoprecipitation, and biochemical 9500 Gilman Drive purification. SIR2 is not itself essential for viability, but La Jolla, California 92093 sir2⌬ null mutants have a number of phenotypes. In addition to transcriptional silencing defects, sir2⌬ strains have increased rates of recombination within Pundits and biologists alike are making much of the rDNA repeats, a phenotype associated with aging in news that the human genome encodes strikingly fewer yeast, and the mutants are defective in the meiotic pa-genes in its billions of base pairs than might have been chytene checkpoint (reviewed in Gottschling, 2000; anticipated. Nonetheless, each of these genes and non-Roeder and Bailis, 2000; Moazed, 2001). coding sequences must be appropriately regulated and Several years ago, as progress from many genome either made accessible to or shielded from the molecular sequencing projects began to accumulate, it became machineries that transact processes of replication, tran-clear that Sir2p was only one member of a very large scription, recombination, and repair. In large part, this family of broadly conserved proteins (Brachmann et al., regulation is mediated in the context of chromatin, the 1995). Even in S. cerevisiae, four additional family mem-packaged form of DNA bound by nucleosomal histones bers, or HST (Homologs of Sir Two) genes were found and other proteins. Although chromatin itself was long that had not been detected previously. Genetic studies regarded as a rather stable or static platform upon which reveal that the genes are not fully redundant, but are other levels of regulation were elaborated, it is increas-instead likely to have distinct functions in vivo. Beyond ingly clear that the assembly of histones into chromatin, yeast, family members exist in essentially every species and the dynamic posttranslational modifications of his-for which extensive sequence data are available. These tones contribute enormously to genomic function and range from the seven homologs in human, to homologs regulation. These observations have led to hypotheses in the Eubacteria and Archaea (Figure 1a). Remarkably, that a " code " of histone modifications, particularly of this family of proteins known to function as chromatin the extended amino-terminal tails, can specify such key regulators in the eukaryotes is therefore more ancient processes as cell cycle regulation and recruitment of even than the nucleosome itself! transcriptional complexes (Strahl and Allis, 2000). Critical insights into the possible mechanism of activ-Indeed, over the last few years, the pages of this …