A Complex Gene Regulatory Mechanism that Operates at the Nexus of Multiple RNA Processing Decisions

McPheeters, David S.; Cremona, Nicole; Sunder, Sham; Chen, Huei-Mei; Averbeck, Nicole; Leatherwood, Janet K.; Wise, Jo Ann

doi:10.1038/nsmb.1556

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A Complex Gene Regulatory Mechanism that Operates at the Nexus of Multiple RNA Processing Decisions

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Author(s): David S. McPheeters ¹ , Nicole Cremona ¹ , Sham Sunder ¹ , Huei-Mei Chen ² , Nicole Averbeck ² , Janet Leatherwood ² , Jo Ann Wise ¹

Publication date (Electronic): 8 February 2009

Journal: Nature structural & molecular biology

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Abstract

Expression of crs1 pre-mRNA, encoding a meiotic cyclin, is blocked in actively growing fission yeast cells by a multifaceted mechanism. The most striking feature is that crs1 transcripts are continuously synthesized in vegetative cells, but are targeted for degradation rather than splicing and polyadenylation. Turnover of crs1 RNA requires the exosome, similar to previously described nuclear surveillance and silencing mechanisms, but does not involve a non-canonical poly(A) polymerase. Instead, crs1 transcripts are targeted for destruction by a factor previously implicated in turnover of meiotic RNAs in growing cells. Like exosome mutants, mmi1 mutants splice and polyadenylate vegetative crs1 transcripts. Two regulatory elements are located at the 3′ end of the crs1 gene, consistent with the increased accumulation of spliced RNA in polyadenylation factor mutants. This highly integrated regulatory strategy may ensure a rapid response to adverse conditions, thereby guaranteeing survival.

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Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution.

Brian T. Wilhelm, Samuel Marguerat, Stephen Watt … (2008)

Recent data from several organisms indicate that the transcribed portions of genomes are larger and more complex than expected, and that many functional properties of transcripts are based not on coding sequences but on regulatory sequences in untranslated regions or non-coding RNAs. Alternative start and polyadenylation sites and regulation of intron splicing add additional dimensions to the rich transcriptional output. This transcriptional complexity has been sampled mainly using hybridization-based methods under one or few experimental conditions. Here we applied direct high-throughput sequencing of complementary DNAs (RNA-Seq), supplemented with data from high-density tiling arrays, to globally sample transcripts of the fission yeast Schizosaccharomyces pombe, independently from available gene annotations. We interrogated transcriptomes under multiple conditions, including rapid proliferation, meiotic differentiation and environmental stress, as well as in RNA processing mutants to reveal the dynamic plasticity of the transcriptional landscape as a function of environmental, developmental and genetic factors. High-throughput sequencing proved to be a powerful and quantitative method to sample transcriptomes deeply at maximal resolution. In contrast to hybridization, sequencing showed little, if any, background noise and was sensitive enough to detect widespread transcription in >90% of the genome, including traces of RNAs that were not robustly transcribed or rapidly degraded. The combined sequencing and strand-specific array data provide rich condition-specific information on novel, mostly non-coding transcripts, untranslated regions and gene structures, thus improving the existing genome annotation. Sequence reads spanning exon-exon or exon-intron junctions give unique insight into a surprising variability in splicing efficiency across introns, genes and conditions. Splicing efficiency was largely coordinated with transcript levels, and increased transcription led to increased splicing in test genes. Hundreds of introns showed such regulated splicing during cellular proliferation or differentiation.

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RNA degradation by the exosome is promoted by a nuclear polyadenylation complex.

John LaCava, Jonathan Houseley, Cosmin Saveanu … (2005)

The exosome complex of 3'-5' exonucleases participates in RNA maturation and quality control and can rapidly degrade RNA-protein complexes in vivo. However, the purified exosome showed weak in vitro activity, indicating that rapid RNA degradation requires activating cofactors. This work identifies a nuclear polyadenylation complex containing a known exosome cofactor, the RNA helicase Mtr4p; a poly(A) polymerase, Trf4p; and a zinc knuckle protein, Air2p. In vitro, the Trf4p/Air2p/Mtr4p polyadenylation complex (TRAMP) showed distributive RNA polyadenylation activity. The presence of the exosome suppressed poly(A) tail addition, while TRAMP stimulated exosome degradation through structured RNA substrates. In vivo analyses showed that TRAMP is required for polyadenylation and degradation of rRNA and snoRNA precursors that are characterized exosome substrates. Poly(A) tails stimulate RNA degradation in bacteria, suggesting that this is their ancestral function. We speculate that this function was maintained in eukaryotic nuclei, while cytoplasmic mRNA poly(A) tails acquired different roles in translation.

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RNA-quality control by the exosome.

Jonathan Houseley, John LaCava, David Tollervey (2006)

The exosome complex of 3'-->5' exonucleases is an important component of the RNA-processing machinery in eukaryotes. This complex functions in the accurate processing of nuclear RNA precursors and in the degradation of RNAs in both the nucleus and the cytoplasm. However, it has been unclear how different classes of substrate are distinguished from one another. Recent studies now provide insights into the regulation and structure of the exosome, and they reveal striking similarities between the process of RNA degradation in bacteria and eukaryotes.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101186374

Journal ID (pubmed-jr-id): 31761

Journal ID (nlm-ta): Nat Struct Mol Biol

Title: Nature structural & molecular biology

ISSN (Print): 1545-9993

ISSN (Electronic): 1545-9985

Publication date Nihms-submitted: 14 April 2009

Publication date (Electronic): 8 February 2009

Publication date (Print): March 2009

Publication date PMC-release: 12 November 2009

Volume: 16

Issue: 3

Pages: 255-264

Affiliations

[1 ]Center for RNA Molecular Biology and Department of Molecular Biology & Microbiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4960

[2 ]Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794-5222

Author notes

Correspondence should be addressed to J.A.W. ( jaw17@ 123456case.edu ) Phone: (216)-368-1876, FAX (216)-368-3055

AUTHOR CONTRIBUTIONS

David McPheeters performed the TRO experiments, designed the real-time PCR assay, and participated in development of the model as well as writing of the manuscript. Nicole Cremona constructed and analyzed the chimeric and mutant alleles of crs1 to define the regulatory element, performed the RNA analyses on trans-acting factor mutants, qPCR, and expertly proofread the manuscript. Sham Sunder analyzed processing of crs1 RNA over a meiotic time course and conducted initial experiments to map the crs1 regulatory element. Nicole Averbeck mapped the crs1 RNA termini by RACE and constructed the crs1 deletion strain. Huei-Mei Chen and Janet Leatherwood discovered the splicing defect in the pfs2-11 mutant. Jo Ann Wise wrote the manuscript and contributed to the design and interpretation of all experiments.

Article

Manuscript ID: nihpa86778

DOI: 10.1038/nsmb.1556

PMC ID: 2776722

PubMed ID: 19198588

SO-VID: 45e329f0-a960-4510-94f9-1da20510033c