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Dicer is required for chromosome segregation and gene silencing in fission yeast cells
Karolinska Institute.
Södertörns högskola, Avdelning Naturvetenskap. Karolinska Institute.
Karolinska Institute.
Södertörns högskola, Avdelning Naturvetenskap. Karolinska Institute.
Vise andre og tillknytning
2002 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, nr 26, s. 16648-16653Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

RNA interference is a form of gene silencing in which the nuclease Dicer cleaves double-stranded RNA into small interfering RNAs. Here we report a role for Dicer in chromosome segregation of fission yeast. Deletion of the Dicer (dcr1(+)) gene caused slow growth, sensitivity to thiabendazole, lagging chromosomes during anaphase, and abrogated silencing of centromeric repeats. As Dicer in other species, Dcr1p degraded double-stranded RNA into approximate to23 nucleotide fragments in vitro, and dcr1Delta cells were partially rescued by expression of human Dicer, indicating evolutionarily conserved functions. Expression profiling demonstrated that dcr1(+) was required for silencing of two genes containing a conserved motif.

sted, utgiver, år, opplag, sider
2002. Vol. 99, nr 26, s. 16648-16653
HSV kategori
Identifikatorer
URN: urn:nbn:se:sh:diva-15719DOI: 10.1073/pnas.212633199ISI: 000180101600028PubMedID: 12482946Scopus ID: 2-s2.0-0037168521OAI: oai:DiVA.org:sh-15719DiVA, id: diva2:508475
Tilgjengelig fra: 2012-03-08 Laget: 2012-03-06 Sist oppdatert: 2017-07-20bibliografisk kontrollert
Inngår i avhandling
1. Histone deacetylases and their co-regulators in schizosaccharomyces pombe
Åpne denne publikasjonen i ny fane eller vindu >>Histone deacetylases and their co-regulators in schizosaccharomyces pombe
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Karolinska Institutet, 2007. s. 37
HSV kategori
Identifikatorer
urn:nbn:se:sh:diva-31262 (URN)978-91-7357-140-1 (ISBN)
Disputas
2007-03-23, MA636, Alfred Nobels allé 7, Huddinge, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-12-01 Laget: 2016-12-01 Sist oppdatert: 2016-12-01bibliografisk kontrollert
2. Characterization of RNA polymerase II subunit Rpb7 in silencing and transcription
Åpne denne publikasjonen i ny fane eller vindu >>Characterization of RNA polymerase II subunit Rpb7 in silencing and transcription
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The DNA in eukaryotes is arranged in fibres of chromatin. The chromatin may be more or less compacted and the degree of condensation of the chromatin affects the accessibility of the DNA. The accessibility of the DNA, in turn, affects transcription and gene regulation. Genes within inaccessible DNA are commonly repressed whereasgenes within accessible DNA are active and expressed. This thesis concerns the interplay between chromatin and transcription with focus on the function of the RNA polymerase II (pol II) subunit Rpb7. We have demonstrated that processing of centromeric transcripts by the ribonuclease III family protein Dcr1 is required for heterochromatin formation at the centromeres of Schizosaccharomyces pombe. A point mutation in the pol II subunit Rpb7 caused a specific defect in centromeric heterochromatin formation. We have shown i) that the centromeric transcripts that accumulate in dcr1delta cells are products of pol II, ii) the rpbG150D mutation is deficient in recognition and/or initiation of transcription from the centromeric promoter. Transcription by pol II within the centromeres was surprising since insertion of marker genes within these loci normally results in repression of pol II transcription. Here, paradoxically, pol II transcription was required for the construction of the inaccessible heterochromatin structure. Our analysis of sRNA in S. pombe revealed that most centromeric siRNA are originating from two clusters, which are repeated several times within the centromeres. This lead us to propose a model in which centromeric transcripts fold into double stranded structures that are processed by Dcr1. The resulting siRNAs may contribute with the starting signal for the RNAi feedback loop required for heterochromatin formation at the centromeres. Finally, we demonstrate that the genome-wide association of Rpb7 is nearly identical to that of the core pol II subunit Rpb2, indicating a general role for Rpb7 in transcription. We further show that the occupancy pattern of Rpb4, a pol II subunit that forms a subcomplex together with Rpb7, differs from those of Rpb2 and Rpb7. Rpb4 may therefore have a less general function in transcription than Rpb7. Hence, transcription by pol II is required not only for gene expression but also for repression via formation of inaccessible heterochromatin.

sted, utgiver, år, opplag, sider
Stockholm: Karolinska Institutet, 2009. s. 55
HSV kategori
Identifikatorer
urn:nbn:se:sh:diva-31550 (URN)978-91-7409-606-4 (ISBN)
Disputas
2009-12-04, Föreläsningssalen, plan 4, NOVUM, Huddinge, 10:00
Opponent
Veileder
Tilgjengelig fra: 2016-12-29 Laget: 2016-12-29 Sist oppdatert: 2016-12-29bibliografisk kontrollert

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Silverstein, Rebecca AWalfridsson, JulianDjupedal, IngelaKniola, BarbaraWright, Anthony P HEkwall, Karl

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