TheSchizosaccharomyces pombe hst4+Gene Is aSIR2Homologue with Silencing and Centromeric Functions

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Abstract
Although silencing is a significant form of transcriptional regulation, the functional and mechanistic limits of its conservation have not yet been established. We have identified theSchizosaccharomyces pombe hst4+gene as a member of the SIR2/HST silencing gene family that is defined in organisms ranging from bacteria to humans.hst4Δ mutants grow more slowly than wild-type cells and have abnormal morphology and fragmented DNA. Mutant strains show decreased silencing of reporter genes at both telomeres and centromeres. hst4+appears to be important for centromere function as well because mutants have elevated chromosome-loss rates and are sensitive to a microtubule-destabilizing drug. Consistent with a role in chromatin structure, Hst4p localizes to the nucleus and appears concentrated in the nucleolus.hst4Δ mutant phenotypes, including growth and silencing phenotypes, are similar to those of the Saccharomyces cerevisiae HSTs, and at a molecular level,hst4+is most similar toHST4. Furthermore, hst4+is a functional homologue of S. cerevisiae HST3 andHST4 in that overexpression ofhst4+rescues the temperature-sensitivity and telomeric silencing defects of an hst3Δ hst4Δdouble mutant. These results together demonstrate that aSIR-like silencing mechanism is conserved in the distantly related yeasts and is likely to be found in other organisms from prokaryotes to mammals.