Sir2p is an NAD ؉ -dependent histone deacetylase required for chromatin-dependent silencing in yeast. In a cell-based screen for inhibitors of Sir2p, we identified a compound, splitomicin, that creates a conditional phenocopy of a sir2 deletion mutant in Saccharomyces cerevisiae. Cells grown in the presence of the drug have silencing defects at telomeres, silent mating-type loci, and the ribosomal DNA. In addition, whole genome microarray experiments show that splitomicin selectively inhibits Sir2p. Portions of the eukaryotic genome can be maintained in a transcriptionally inactive, or silenced, state as the result of the local chromatin structure. Silent chromatin may encompass regions ranging from a few thousand base pairs, as in the silent mating-type genes of the yeast Saccharomyces cerevisiae (1), to whole chromosomes such as the inactive X chromosome in mammals (2). The formation of silent chromatin, which is best understood at the S. cerevisiae silent mating-type loci HMR and HML, and telomeres depends on DNA elements, or silencers. The HM silencers are located in proximity to the genes that they regulate and contain a combination of binding sites for Rap1p, Abf1p, and the origin recognition complex (1). These proteins recruit the SIR (silent information regulator) protein complex (Sir2p-4p) through protein-protein interactions. Once recruited to silencers, the SIR complex is thought to spread along the chromatin through binding of Sir3p and Sir4p to the NH 2 -terminal tails of histone H3 and H4 (reviewed in ref. 3). Among the many requirements for silent chromatin (reviewed in ref. 4), posttranslational modification (i.e., acetylation, phosphorylation, methylation, and ubiquitination) of histones seems to be critical. For example, the NH 2 -terminal tails of histones H3 and H4 are hypoacetylated in silent chromatin compared with other regions of the genome (5). Of the SIR proteins, Sir2p has been shown to be an NAD ϩ -dependent histone deacetylase and is responsible for the hypoacetylated state of histones in silent chromatin (6-9). Sir2p also acts at the rRNA-encoding DNA (rDNA) in the RENT protein complex, which does not include Sir3p or Sir4p (10).The yeast SIR2 gene is the defining member of a broadly conserved family of NAD ϩ -dependent deacetylases found in organisms ranging from bacteria to humans (11). In S. cerevisiae alone four additional homologues have been identified (see below). However, it shares the greatest similarity with genes found in other eukaryotes, where it is believed that these closely related homologues serve a comparable role in silencing. Interestingly, SIR2 and its homologues have been implicated in the genetic regulation of aging in both yeast and Caenorhabditis elegans (12, 13) and in metazoan development (M. I. Rosenberg and S. M. Parkhurst, personal communication), although the details of how it affects these fundamental processes are still mysterious.To provide a new tool to dissect the functional role of Sir2p in vivo further, we undertook a phenotypic screen for sma...
The title of this paper derives from two sets of observations. The first, from Lipset and Rokkan, asserts that Western party systems reflect (or, at least, reflected in the mid-1960s) a congealment of political conflicts dating from the 1920s or earlier. The second, taken generally from the growing concern about political ungovernability, suggests that contemporary party systems are losing their capacity to structure choice effectively in Western polities. Since it is one of the defects of frozen food storage that any food, no matter how well frozen, will eventually become unappetizing if not downright unwholesome, it is worth enquiring whether the two sets of observations are interconnected. In a fast-changing world, party systems reflecting the shape of conflict over past problems may appear to the voter as out of touch with newer problems. Indeed, the party systems observed by Lipset and Rokkan have all been challenged subsequently by new forces.
The various subtables of Table i, or some variant of them, must be familiar to every teacher and to every student of Canadian voting behaviour. While most of our history books, and certainly all of our current concerns, focus on cultural differences in Canada, all our voting and party identification data suggest that the primary line of political division is between Roman Catholics and non-Catholics. The leftmost tables in the two rows of Table i indicate that religious differences are approximately three times as strong as ethnic ones, regardless of the index chosen. The percentage difference in Liberal identifiers is 20 across religious categories, but only 6 across the ethnic ones; the phi coefficient is.21 as compared to.06, while Yule's Q is.42 as opposed to.13. Nor is this simply an artifact. The same finding shows up for vote as for party identification, for a linguistic dichotomy as for an ethnicity dichotomy, and for undichotomized as for dichotomized variables. Similarly, the religious dichotomy need not be imposed, but emerges quite freely when similar data are analysed with the aid program. Indeed, one need not depend on using dichotomies at all, though the analysis becomes more complex. In each case, however, the basic generalization holds.
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