Silent information regulators, or Sir proteins, play distinct roles in chromatin-mediated transcriptional control at the silent mating-type loci, telomeres, and within the rDNA repeats of ...Saccharomyces cerevisiae. An unusual collection of sir3 mutant alleles was identified in a genetic screen for enhancers of the sir1 mutant mating-defective phenotype. These sir3-eso mutants, like the sir1 mutant, exhibit little or no mating defects alone, but the sir1 sir3-eso double mutants are essentially nonmating. All of the sir3-eso mutants are defective in telomeric silencing. In some mutants, this phenotype is suppressed by tethering Sir1p to telomeres; other mutants are dominant for mating and telomeric silencing defects. Additionally, several sir3-eso mutants are nonmating in combination with the nat1 N-terminal acetyltransferase mutant. The temperature-sensitive allele sir3-8 has an eso phenotype at permissive temperature, yet acts as a null allele at restrictive temperature due to loss of sir3-8 protein. Sequence analysis showed that eight of the nine sir3-eso alleles have mutations within the N-terminal region that is highly similar to the DNA replication initiation protein Orc1p. Together, these data reveal modular domains for Sir3p and further define its function in silencing chromatin.
Epigenetic transcriptional states are controlled in large part through chromatin modification. Epigenetically silenced regions in yeast were first recognized to be regulated by the SIR1‐4 genes. Of ...these, SIR2 and its homologs are now known to encode NAD‐dependent protein deacetylases (NAD‐DACs) with connections to processes as diverse as metabolic sensing, cellular aging, and pathogenic virulence. Since the discovery of the SIR genes, a growing number of other epigenetic modifiers have been identified, many of which have distinct catalytic activities. Some of these directly modify histones and other substrates to influence transcription, whereas others have clear roles in chromatin assembly, remodeling, repair and recombination. Mutational analyses reveal that many of these epigenetic modifiers at first blush have seemingly minor roles in normal cellular physiology. However, several of them functionally interact and their cumulative loss can lead to cell death. Our studies of the NAD‐DACs, acetyltransferases (ATs) and methyltransferases (MTs) have uncovered new epigenetic modifiers with previously unsuspected roles in transcriptional silencing. Critical interactions will be defined between ATs and MTs, and an enhancer that results in stress‐induced lethality of sir2Δ mutants.
Even when we know the primary sequences and binding specificities of every transcriptional activator and repressor, our understanding of transcriptional regulation will be rudimentary. This is partly ...because major aspects of gene expression are governed by epigenetic mechanisms. These mechanisms may be responsible for apparently identical sequences being read by the transcriptional machinery in two different but heritable ways: active or repressed. Epigenetic transcriptional states have been encountered in a number of recent experiments.
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