Termination of Cryptic Unstable Transcripts Is Directed by Yeast RNA-Binding Proteins Nrd1 and Nab3

Arigo, John T.; Eyler, Daniel E.; Carroll, Kristina L.; Corden, Jeffry L.

doi:10.1016/j.molcel.2006.07.024

Cited by 238 publications

(258 citation statements)

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“…Alternatively, the recruitment of the exosome could be constitutive and independent of specific processing events. For instance, the degradation of cryptic unstable transcripts in S. cerevisiae is closely coupled to the Nrd1p-Nab3p-dependent transcription termination pathway (Arigo et al, 2006;Thiebaut et al, 2006). Our results suggest, in contrast, that protein-coding genes in insects are monitored by a constitutive mechanism.…”

Section: Discussionmentioning

confidence: 76%

The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Hessle¹,

Björk²,

Sokolowski³

et al. 2009

MBoC

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Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins. INTRODUCTIONExpression of protein-coding genes is a complex multistep process. Precursor messenger RNAs (pre-mRNAs) are synthesized by RNA polymerase II (Pol-II) and assembled into ribonucleoprotein (RNP) complexes during transcription. The pre-mRNPs must be processed to become mature mRNPs, which are exported to the cytoplasm and translated into protein. Mutations in the DNA or errors in the transcription and processing reactions can lead to the synthesis of aberrant mRNPs. Eukaryotic cells have evolved quality control mechanisms that identify aberrant mRNPs and prevent their expression into protein. In the yeast Saccharomyces cerevisiae there are at least three nuclear steps of mRNP biogenesis that are under surveillance: the cleavage and polyadenylation of the 3Ј end (Hilleren et al., 2001), the assembly of the mRNA-protein complexes (Zenklusen et al., 2002;Luna et al., 2005), and the removal of introns (Galy et al., 2004). In all cases, mRNPs with assembly and/or processing defects are detected by nuclear surveillance mechanisms, retained in the nucleus, and degraded (reviewed by Vinciguerra and Stutz, 2004;Sommer and Nehrbass, 2005;Saguez et al., 2005). Genetic studies in S. cerevisiae have identified the nuclear exosome as a key player in the recognition and retention of defective transcripts (reviewed by Jensen et al., 2003;Houseley et al., 2006;Vanacova and Stefl, 2007;Schmid and Jensen, 2008).The exosome is a protein complex with ribonuclease activity (Mitchell et al., 1997;Allmang et al., 1999;Mitchell and Tollervey, 2000). The core of the exosome has a barrel-like architecture (reviewed by Lorentzen et al., 2008). The barrel is made of nine protein subunits organized into two rings, a hexameric ring and a trimeric ring, and the structure of the barrel is conserved throughout evolution (Lorentzen et al., 2005;Liu et al., 2006;Wang et al., 2007). Two additional proteins, Dis3/Rrp44 and R...

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Section: Discussionmentioning

confidence: 76%

The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Hessle¹,

Björk²,

Sokolowski³

et al. 2009

MBoC

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“…These transcripts are estimated to originate from 10% of yeast intergenic regions (Wyers et al 2005; although see Neil et al 2009 andXu et al 2009). After Nrd1-dependent termination by RNAPII, CUTs are rapidly polyadenylated by the TRAMP complex, and then degraded by the nuclear exosome (Wyers et al 2005;Arigo et al 2006b;Houalla et al 2006;Thiebaut et al 2006). Recently, Gudipati et al (2008) showed that Nrd1-dependent termination of CUTs is inhibited by CTD phosphorylation on Ser2 and promoted by Ser5 phosphorylation.…”

Section: A Wider Role For the Nrd1 Complex In Gene Expressionmentioning

confidence: 99%

Transcription termination by nuclear RNA polymerases

Richard

Manley²

2009

Genes Dev.

291

326

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Gene transcription in the cell nucleus is a complex and highly regulated process. Transcription in eukaryotes requires three distinct RNA polymerases, each of which employs its own mechanisms for initiation, elongation, and termination. Termination mechanisms vary considerably, ranging from relatively simple to exceptionally complex. In this review, we describe the present state of knowledge on how each of the three RNA polymerases terminates and how mechanisms are conserved, or vary, from yeast to human.

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“…Non-coding RNAs found upstream of known protein coding genes in yeast are termed cryptic unstable transcripts (CUTs). Both the Nrd1/Nab3/Sen1 complex, which binds CUTs in a sequence dependent manner, 14 and modification of CUTs by addition of a short polyA tract by the Trf-Air-Mtr4 polyadenylation (TRAMP) complex activate exosome-mediated degradation. 15,16 This exosome-dependent degradation explains why the CUTs are rarely seen in genomic assays.…”

Section: Divergent Transcription In Mammalsmentioning

confidence: 99%