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A new role for the transcriptional corepressor SIN3; Regulation of centromeres
Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
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2003 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 13, no 1, 68-72 p.Article in journal (Refereed) Published
Abstract [en]

Centromeres play a vital role in maintaining the genomic stability of eukaryotes by coordinating the equal distribution of chromosomes to daughter cells during mitosis and meiosis. Fission yeast (S. pombe) centromeres consist of a 4-9 kb central core region and 30-100 kb of flanking inner (imr/B) and outer (otr/K) repeats [1-3]. These sequences direct a laminar kinetochore structure similar to that of human centromeres [4, 5]. Centromeric heterochromatin is generally underacetylated [6, 7]. We have previously shown that inhibition of histone deacetylases (HDACs) caused hyperacetylation of centromeres and defective chromosome segregation [8]. SIN3 is a HDAC corepressor that has the ability to mediate HDAC targeting in the repression of promoters. In this study, we have characterized S. pombe sin three corepressors (Pst1p and Pst2p) to investigate whether SIN3-HDAC is required in the regulation of centromeres. We show that only pst1-1 and not pst2Delta cells displayed anaphase defects and thiabendazole sensitivity. pst1-1 cells showed reduced centromeric silencing, increased histone acetylation in centromeric chromatin, and defective centromeric sister chromatid cohesion. The HDAC Clr6p and Pst1p coimmunoprecipitated, and Pst1p colocalized with centromeres, particularly in binucleate cells. These data are consistent with a model in which Pst1 pClr6p temporally associate with centromeres to carry out the initial deacetylation necessary for subsequent steps in heterochromatin formation.

Place, publisher, year, edition, pages
2003. Vol. 13, no 1, 68-72 p.
National Category
Biochemistry and Molecular Biology Cell Biology
URN: urn:nbn:se:sh:diva-17667DOI: 10.1016/S0960-9822(02)01401-XISI: 000180915600025PubMedID: 12526748ScopusID: 2-s2.0-0346034996OAI: diva2:577065
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2016-12-01Bibliographically approved
In thesis
1. Histone deacetylases and their co-regulators in schizosaccharomyces pombe
Open this publication in new window or tab >>Histone deacetylases and their co-regulators in schizosaccharomyces pombe
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The DNA in every eukaryotic cell is wrapped around eight core histones to form the nucleosome. Therefore all events that involve DNA must also involve chromatin and nucleosomes. By regulating chromatin structure the cell can regulate the reactivity of the DNA. One of the most common ways of altering nucleosomes is the acetylation of lysine residues. Two enzymes are required to maintain the correct equilibrium for optimal cell growth: histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs). In general, histone hypoacetylation is correlated with transcriptional inactivation, while hyperacetylation is correlated with active gene transcription. In Schizosaccharomyces pombe, mating type loci are silenced. Deletion of HDAC Hos2 had previously been shown to slightly increase silencing at the mating type locus. To assess whether any other HDAC was necessary for mating type silencing, cells were treated with HDAC poison Trichostatin A (TSA). TSA was found to cause a mild derepression of the mating type locus, indicating that another HDAC was responsible for silencing in this region. The RNA interference nuclease Dcr1 was later identified, and showed to degrade double stranded RNA into small nucleotide fragments. Deletion of dcr1 caused chromosome segregation defects and derepression of centromeric silencing. Rpd3 in S. cerevisiae is recruited to genomic targets by interacting with co-regulator Sin3. S. pombe has three Sin3 homologs. Pst1 interacts with the HDAC Clr6, and like Clr6 is an essential gene, mutants of which display chromosome mis-segregation and derepression of centromeric silencing. Pst1 was required for centromeric cohesion, and localized to centromeres in late S phase. Thus a co-repressor paradigm could be applied to centromere silencing as well. A comparative characterization of HDACs in S. pombe showed that the HDACs had different localizations and histone specificities. The comparison of HDACs was taken further with a genome wide expression analysis and histone density study of mutants. Results indicated that Clr6 was most often involved in promoter initiated gene repression, whereas Hos2 promoted the high expression of growth related genes by deacetylating H4K16ac in their coding regions. A class II HDAC, Clr3, was found to act cooperatively with Sir2 throughout the genome. Using a genomic approach to analyze Pst3, it was established that Clr6 and Pst3 could cooperate to negatively regulate genes by binding to their promoter regions. On the other hand, Pst3 was also involved in the up-regulation of ribosome biosynthesis genes, and could bind to the rDNA.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet, 2007. 37 p.
National Category
Biological Sciences
urn:nbn:se:sh:diva-31262 (URN)978-91-7357-140-1 (ISBN)
Public defence
2007-03-23, MA636, Alfred Nobels allé 7, Huddinge, 13:00 (English)
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2016-12-01Bibliographically approved

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