Fission Yeast Cid12 Has Dual Functions in Chromosome Segregation and Checkpoint Control

Win, Thein Z.; Stevenson, Abigail L.; Wang, Shao-Win

doi:10.1128/mcb.02205-05

Cited by 20 publications

(23 citation statements)

References 57 publications

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“…Some members of the family have been implicated to have function(s) in RNA silencing pathways in other organisms. Substitution of putative active site residues of S. pombe Cid12 disrupts RNAi-dependent heterochromatin formation and accumulation of centromeric siRNAs (Win et al 2006). S. pombe Cid14, the ortholog of Saccharomyces cerevisiae Trf4/5, also functions in heterochromatic gene silencing ).…”

Section: Discussionmentioning

confidence: 99%

A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis

Lee

Talsky²,

Collins³

2009

RNA

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Members of the conserved family of eukaryotic RNA-dependent RNA polymerases (Rdrs) synthesize double-stranded RNA (dsRNA) intermediates in diverse pathways of small RNA (sRNA) biogenesis and RNA-mediated silencing. Rdr-dependent pathways of sRNA production are poorly characterized relative to Rdr-independent pathways, and the Rdr enzymes themselves are poorly characterized relative to their viral RNA-dependent RNA polymerase counterparts. We previously described a physical and functional coupling of the Tetrahymena thermophila Rdr, Rdr1, and a Dicer enzyme, Dcr2, in the production of ;24-nucleotide (nt) sRNA in vitro. Here we characterize the endogenous complexes that harbor Rdr1, termed RDRCs. Distinct RDRCs assemble to contain Rdr1 and subsets of the total of four tightly Rdr1-associated proteins. Of particular interest are two RDRC subunits, Rdn1 and Rdn2, which possess noncanonical ribonucleotidyl transferase motifs. We show that the two Rdn proteins are uridine-specific polymerases of separate RDRCs. Two additional RDRC subunits, Rdf1 and Rdf2, are present only in RDRCs containing Rdn1. Rdr1 catalytic activity is retained in RDRCs purified from cell extracts lacking any of the nonessential RDRC subunits (Rdn2, Rdf1, Rdf2) or if the RDRC harbors a catalytically inactive Rdn. However, specific disruption of each RDRC imposes distinct loss-of-function consequences at the cellular level and has a differential impact on the accumulation of specific 23-24-nt sRNA sequences in vivo. The biochemical and biological phenotypes of RDRC subunit disruption reveal a previously unanticipated complexity of Rdr-dependent sRNA biogenesis in vivo.

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Section: Discussionmentioning

confidence: 99%

A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis

Lee

Talsky²,

Collins³

2009

RNA

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“…Cells lacking Cid14 or mutant cells defective in the Dis3/Rpr44 component of the exosome accumulate polyadenylated transcripts corresponding to naturally silenced repeat elements within heterochromatic domains, with consequent defects in centromeric gene silencing. Based on these data, we propose a role for Cid14 in stimulating the degradation of these transcripts to ensure heterochromatic function, which is distinct from the function of Cid12 in RNAi-mediated heterochromatin assembly (19,37) and from previously suggested models of Cid14 function (3). …”

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confidence: 99%

“…We also uncover roles for Cid14 and Dis3 in maintaining the genomic integrity of ribosomal DNA. Our data indicate that polyadenylation-assisted nuclear RNA turnover functions in eliminating a variety of RNA targets to control diverse processes, such as heterochromatic gene silencing, meiotic differentiation, and maintenance of genomic integrity.Polyadenylation is important for the maturation of mRNAs (26), while our recent work has also uncovered unexpected links between polyadenylation and chromosome replication and segregation (33,35,37). In addition to its function in the maturation of mRNAs, nuclear polyadenylation is important for diverse cellular activities, such as RNA interference (RNAi)-mediated heterochromatin assembly and quality control of noncoding RNAs (33,35,37).…”

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confidence: 99%

“…These functions involve Cid12 and Cid14, members of a widespread family of noncanonical poly(A) polymerases found in eukaryotes from yeasts to humans (30). Besides its function in checkpoint control, Cid12 is required for faithful chromosome segregation and RNAi-mediated heterochromatin assembly at centromeres (19,37). RNAi silencing is triggered by double-stranded RNA, which is processed by the RNase III-like RNase Dicer into small interfering RNA (siRNA) molecules of around 21 nucleotides.…”

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confidence: 99%

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Global Role for Polyadenylation-Assisted Nuclear RNA Degradation in Posttranscriptional Gene Silencing

Wang

Stevenson

Kearsey

et al. 2008

Molecular and Cellular Biology

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Fission yeast Cid14, a component of the TRAMP (Cid14/Trf4-Air1-Mtr4 polyadenylation) complex, polyadenylates nuclear RNA and stimulates degradation by the exosome for RNA quality control. Here, we analyze patterns of global gene expression in cells lacking the Cid14 or the Dis3/Rpr44 subunit of the nuclear exosome. We found that transcripts from many genes induced during meiosis, including key regulators, accumulated in the absence of Cid14 or Dis3. Moreover, our data suggest that additional substrates include transcripts involved in heterochromatin assembly. Mutant cells lacking Cid14 and/or Dis3 accumulate transcripts corresponding to naturally silenced repeat elements within heterochromatic domains, reflecting defects in centromeric gene silencing and derepression of subtelomeric gene expression. We also uncover roles for Cid14 and Dis3 in maintaining the genomic integrity of ribosomal DNA. Our data indicate that polyadenylation-assisted nuclear RNA turnover functions in eliminating a variety of RNA targets to control diverse processes, such as heterochromatic gene silencing, meiotic differentiation, and maintenance of genomic integrity.Polyadenylation is important for the maturation of mRNAs (26), while our recent work has also uncovered unexpected links between polyadenylation and chromosome replication and segregation (33,35,37). In addition to its function in the maturation of mRNAs, nuclear polyadenylation is important for diverse cellular activities, such as RNA interference (RNAi)-mediated heterochromatin assembly and quality control of noncoding RNAs (33,35,37). These functions involve Cid12 and Cid14, members of a widespread family of noncanonical poly(A) polymerases found in eukaryotes from yeasts to humans (30). Besides its function in checkpoint control, Cid12 is required for faithful chromosome segregation and RNAi-mediated heterochromatin assembly at centromeres (19,37). RNAi silencing is triggered by double-stranded RNA, which is processed by the RNase III-like RNase Dicer into small interfering RNA (siRNA) molecules of around 21 nucleotides. These siRNAs become incorporated into the RNAinduced transcriptional silencing (RITS) complex, directing the complex to homologous RNA targets (6). In worms, plants, and fungi, RNAi also requires RNA-directed RNA polymerases (RDRs), which are involved in the siRNA-and template-directed production of double-stranded RNA (1, 17, 29). Motamedi et al. (19) identified Cid12 in an RDR complex (RDRC) which also contains Rdp1 (the fission yeast RDR homolog) and Hrr1 (an RNA helicase). RDRC physically interacts with the RITS complex in a manner that requires Dicer and the histone methyltransferase Clr4. In cells lacking Cid12, RITS complexes are devoid of siRNA and fail to localize to centromeric DNA repeats to initiate heterochromatin assembly.In Saccharomyces cerevisiae, the Cid1-like proteins Trf4 and Trf5 share an essential function that involves the polyadenylation of nuclear RNAs as part of a pathway of exosomemediated RNA turnover (10,12,31,38). We have ide...

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“…Remarkably, Clr4 is required for the interaction between RITS and RDRC, suggesting that RITS and RDRC might only be able to interact in a heterochromatic context. Both RITS and RDRC are continuously required to maintain silencing of the pericentromeric region (Volpe et al, 2002) and for pericentromeric structure; mutation of RITS or RDRC components was shown to lead to increased errors in chromosome segregation due to premature loss of centromeric cohesion (Volpe et al, 2003;Win et al, 2006). Nevertheless, two sets of experiments have shown that, in the end, most RNAi factors are dispensable for centromere function.…”

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The role of small non-coding RNAs in genome stability and chromatin organization

Wolfswinkel

Ketting

2010

Journal of Cell Science

102

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SummarySmall non-coding RNAs make up much of the RNA content of a cell and have the potential to regulate gene expression on many different levels. Initial discoveries in the 1990s and early 21st century focused on determining mechanisms of post-transcriptional regulation mediated by small-interfering RNAs (siRNAs) and microRNAs (miRNAs). More recent research, however, has identified new classes of RNAs and new regulatory mechanisms, expanding the known regulatory potential of small non-coding RNAs to encompass chromatin regulation. In this Commentary, we provide an overview of these chromatin-related mechanisms and speculate on the extent to which they are conserved among eukaryotes.Key words: Argonaute, Chromatin, Germ cell, Methylation, piRNA, siRNA Journal of Cell Scienceby proteins that have a bromodomain and is associated with active transcription. Conversely, lysine methylation can be associated with either activation or repression of transcription, depending on the exact site of the mark. Methylation of lysine 9 of histone 3 (H3K9me) can be recognized by chromodomain proteins, such as heterochromatin protein 1 (HP1), which recruits deacetylating activity to the locus and induces packaging into inactive heterochromatin. Methylated lysine 4 of the same histone (H3K4me) can be bound by double-chromodomain proteins, such as CHD1, or by plant homeodomain (PHD) proteins, and recruits enzymatic activities that promote active, open chromatin. It is, however, important to note that the effect of a histone modification is highly dependent on its total context -it is too simplistic to regard individual modifications as being activating or repressing. In the context of small-RNA-induced chromatin modification, the H3K9 methylation has been best described. This modification is recognized by the RNA-induced transcriptional silencing (RITS) complex, as will be discussed below.Although not common to all eukaryotes, methylation of DNA itself constitutes a more stable type of modification than histone modification. Cytosines, particularly those in a CpG context, can be methylated in the DNA of plants and mammals. CpG methylation is symmetrical and found in both sister chromatids following genome duplication. Non-CpG methylation often is asymmetrical and must be readjusted after every cell division to be maintained, and is therefore less stable than symmetrical methylation. Non-CpG methylation has mainly been described in plants. Both types of DNA methylation generally induce the formation of compact, inactive chromatin, although in plants some methylation of open reading frames is associated with active transcription (for a review, see Munshi et al., 2009;Quina et al., 2006). Control of transposable elementsTransposable elements were first discovered in the 1940s (McClintock, 1950) and are now known to make up a large portion of the genomes of most organisms. For example, 10% of the Arabidopsis genome consists of transposons and transposon remains, and transposons account for 45% of the sequence of the human genome. The a...

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Fission Yeast Cid12 Has Dual Functions in Chromosome Segregation and Checkpoint Control

Cited by 20 publications

References 57 publications

A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis

A single RNA-dependent RNA polymerase assembles with mutually exclusive nucleotidyl transferase subunits to direct different pathways of small RNA biogenesis

Global Role for Polyadenylation-Assisted Nuclear RNA Degradation in Posttranscriptional Gene Silencing

The role of small non-coding RNAs in genome stability and chromatin organization

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