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The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats.

ABSTRACT: Maintenance of specific heterochromatic domains is crucial for genome stability. In eukaryotic cells, a fraction of the tandem-repeated ribosomal RNA (rRNA) genes is organized in the heterochromatic structures. The principal determinant of rDNA silencing is the nucleolar remodelling complex, NoRC, that consists of TIP5 (TTF-1-interacting protein-5) and the ATPase SNF2h. Here we showed that TIP5 not only mediates the establishment of rDNA silencing but also the formation of perinucleolar heterochromatin that contains centric and pericentric repeats. Our data indicated that the TIP5-mediated heterochromatin is indispensable for stability of silent rRNA genes and of major and minor satellite repeats. Moreover, depletion of TIP5 impairs rDNA silencing, upregulates rDNA transcription levels and induces cell transformation. These findings point to a role of TIP5 in protecting genome stability and suggest that it can play a role in the cellular transformation process.

SUBMITTER: Guetg C

PROVIDER: S-EPMC2905252 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats.

Guetg Claudio C Lienemann Philipp P Sirri Valentina V Grummt Ingrid I Hernandez-Verdun Danièle D Hottiger Michael O MO Fussenegger Martin M Santoro Raffaella R

The EMBO journal 20100218 13

Maintenance of specific heterochromatic domains is crucial for genome stability. In eukaryotic cells, a fraction of the tandem-repeated ribosomal RNA (rRNA) genes is organized in the heterochromatic structures. The principal determinant of rDNA silencing is the nucleolar remodelling complex, NoRC, that consists of TIP5 (TTF-1-interacting protein-5) and the ATPase SNF2h. Here we showed that TIP5 not only mediates the establishment of rDNA silencing but also the formation of perinucleolar heteroch ...[more]

PMID: 20168299

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Project description:BackgroundTandem repeats are ubiquitous and abundant in higher eukaryotic genomes and constitute, along with transposable elements, much of DNA underlying centromeres and other heterochromatic domains. In maize, centromeric satellite repeat (CentC) and centromeric retrotransposons (CR), a class of Ty3/gypsy retrotransposons, are enriched at centromeres. Some satellite repeats have homology to retrotransposons and several mechanisms have been proposed to explain the expansion, contraction as well as homogenization of tandem repeats. However, the origin and evolution of tandem repeat loci remain largely unknown.ResultsCRM1TR and CRM4TR are novel tandem repeats that we show to be entirely derived from CR elements belonging to two different subfamilies, CRM1 and CRM4. Although these tandem repeats clearly originated in at least two separate events, they are derived from similar regions of their respective parent element, namely the long terminal repeat (LTR) and untranslated region (UTR). The 5' ends of the monomer repeat units of CRM1TR and CRM4TR map to different locations within their respective LTRs, while their 3' ends map to the same relative position within a conserved region of their UTRs. Based on the insertion times of heterologous retrotransposons that have inserted into these tandem repeats, amplification of the repeats is estimated to have begun at least ~4 (CRM1TR) and ~1 (CRM4TR) million years ago. Distinct CRM1TR sequence variants occupy the two CRM1TR loci, indicating that there is little or no movement of repeats between loci, even though they are separated by only ~1.4 Mb.ConclusionsThe discovery of two novel retrotransposon derived tandem repeats supports the conclusions from earlier studies that retrotransposons can give rise to tandem repeats in eukaryotic genomes. Analysis of monomers from two different CRM1TR loci shows that gene conversion is the major cause of sequence variation. We propose that successive intrastrand deletions generated the initial repeat structure, and gene conversions increased the size of each tandem repeat locus.

Project description:Formation of centromeric heterochromatin in fission yeast requires the combined action of chromatin modifying enzymes and small RNAs derived from centromeric transcripts. Positive feedback mechanisms that link the RNAi pathway and the Clr4/Suv39h1 histone H3K9 methyltransferase complex (Clr-C) result in requirements for H3K9 methylation for full siRNA production and for siRNA production to achieve full histone methylation. Nonetheless, it has been proposed that the Argonaute protein, Ago1, is the key initial trigger for heterochromatin assembly via its association with Dicer-independent "priRNAs." The RITS complex physically links Ago1 and the H3-K9me binding protein Chp1. Here we exploit an assay for heterochromatin assembly in which loss of silencing by deletion of RNAi or Clr-C components can be reversed by re-introduction of the deleted gene. We showed previously that a mutant version of the RITS complex (Tas3(WG)) that biochemically separates Ago1 from Chp1 and Tas3 proteins permits maintenance of heterochromatin, but prevents its formation when Clr4 is removed and re-introduced. Here we show that the block occurs with mutants in Clr-C, but not mutants in the RNAi pathway. Thus, Clr-C components, but not RNAi factors, play a more critical role in assembly when the integrity of RITS is disrupted. Consistent with previous reports, cells lacking Clr-C components completely lack H3K9me2 on centromeric DNA repeats, whereas RNAi pathway mutants accumulate low levels of H3K9me2. Further supporting the existence of RNAi-independent mechanisms for establishment of centromeric heterochromatin, overexpression of clr4(+) in clr4?ago1? cells results in some de novo H3K9me2 accumulation at centromeres. These findings and our observation that ago1? and dcr1? mutants display indistinguishable low levels of H3K9me2 (in contrast to a previous report) challenge the model that priRNAs trigger heterochromatin formation. Instead, our results indicate that RNAi cooperates with RNAi-independent factors in the assembly of heterochromatin.

Dataset Information

The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats.

Publications

The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats.

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