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Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states
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dc.contributor.author | Kueng, Stephanie | |
dc.contributor.author | Tsai-Pflugfelder, Monika | |
dc.contributor.author | Oppikofer, Mariano | |
dc.contributor.author | Ferreira, Helder C. | |
dc.contributor.author | Roberts, Emma | |
dc.contributor.author | Tsai, Chinyen | |
dc.contributor.author | Roloff, Tim-Christoph | |
dc.contributor.author | Sack, Ragna | |
dc.contributor.author | Gasser, Susan M. | |
dc.date.accessioned | 2013-12-04T10:01:04Z | |
dc.date.available | 2013-12-04T10:01:04Z | |
dc.date.issued | 2012-05 | |
dc.identifier | 55082519 | |
dc.identifier | 6e52f201-63d9-4cc7-a040-d6668caaa948 | |
dc.identifier | 000304864000052 | |
dc.identifier | 84863714434 | |
dc.identifier.citation | Kueng , S , Tsai-Pflugfelder , M , Oppikofer , M , Ferreira , H C , Roberts , E , Tsai , C , Roloff , T-C , Sack , R & Gasser , S M 2012 , ' Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states ' , PLoS Genetics , vol. 8 , no. 5 , e1002727 . https://doi.org/10.1371/journal.pgen.1002727 | en |
dc.identifier.issn | 1553-7404 | |
dc.identifier.other | ORCID: /0000-0001-9143-504X/work/47356688 | |
dc.identifier.uri | https://hdl.handle.net/10023/4247 | |
dc.description | The Gasser laboratory is supported by the Novartis Research Foundation and the EU training network Nucleosome 4D. SK was supported by an EMBO long-term fellowship, a Schrodinger fellowship from the FWF, and the Swiss SystemsX.ch initiative/C-CINA; HCF by an EMBO long-term fellowship. | en |
dc.description.abstract | Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner. | |
dc.format.extent | 19 | |
dc.format.extent | 2597161 | |
dc.language.iso | eng | |
dc.relation.ispartof | PLoS Genetics | en |
dc.subject | Histone deacetylation | en |
dc.subject | Phosphorylation sites | en |
dc.subject | In-vitro | en |
dc.subject | Yeast silent chromatin | en |
dc.subject | Transcriptional activation | en |
dc.subject | Saccharomyces-cerevisiae telomeres | en |
dc.subject | Cell-cycle | en |
dc.subject | Mating-type loci | en |
dc.subject | Mediated repression | en |
dc.subject | Drosophila embryos | en |
dc.subject | QH426 Genetics | en |
dc.subject.lcc | QH426 | en |
dc.title | Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | https://doi.org/10.1371/journal.pgen.1002727 | |
dc.description.status | Peer reviewed | en |
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