Substrate discrimination and quality control require each catalytic activity of TRAMP and the nuclear RNA exosome

Das, Mom; Zattas, Dimitrios; Zinder, John C.; Wasmuth, Elizabeth V.; Henri, Julien; Lima, Christopher D.

doi:10.1073/pnas.2024846118

Cited by 9 publications

(8 citation statements)

References 84 publications

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“…Mtr4 is recruited to the exosome by Rrp47 and directly interacts with Rrp47 and binding partner Rrp6 at the exosome (64). Mtr4 adenylation activity also competes with Rrp6 deadenylation activity to determine how, depending on transcript stability, RNAs are processed or degraded (43). These connections to Rrp6 could impact Rrp6 function, core exosome function, or both.…”

Section: Discussionmentioning

confidence: 99%

“…We also overexpressed genes encoding members of the nuclear TRAMP complex: Trf4, Trf5, Air1, Air2, and Mtr4. The TRAMP complex is responsible for polyadenylation of transcripts targeted for degradation by the RNA exosome (42,43). We also overexpressed cytoplasmic RNA exosome cofactors Dom34 and Hbs1, which comprise the Dom34-Hbs1 ribosome dissociation complex that releases stalled ribosomes from aberrantly processed mRNAs (44)(45)(46).…”

Section: Specific Rna Exosome Cofactors Suppress the Growth Defect Of...mentioning

confidence: 99%

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The RNA binding protein Nab2 genetically interacts with multiple RNA exosome cofactors to regulate target RNAs

Kinney

Mills-Lujan

Fasken

et al. 2022

Preprint

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RNA binding proteins play important roles in the processing and precise regulation of RNAs. Highlighting the biological importance of RNA binding proteins is the increasing number of human diseases that result from mutations in genes that encode these proteins. We recently discovered that mutations in the ZC3H14 gene, which encodes an evolutionarily conserved polyadenosine RNA-binding protein, cause intellectual disability. Studies of the budding yeast orthologue of ZC3H14, Nuclear Poly(A) Binding protein 2 (Nab2), have provided insight into the functions of this protein. The NAB2 gene is essential in S. cerevisiae, and conditional nab2 mutants cause defects in a number of steps in RNA processing. To explore the critical functions of the Nab2/ZC3H14 protein family, we performed a high-copy suppressor screen on nab2 mutant cells. This screen identified genes encoding two core subunits of the RNA exosome, as well as Nrd1 and Ski7, nuclear and cytoplasmic cofactors of the RNA exosome, respectively. Nrd1 is an RNA binding protein that is part of the Nrd1-Nab3-Sen1 (NNS) complex, which plays an important role in transcription termination of non-coding RNAs. Ski7 is a GTP-binding protein that mediates interaction between the RNA exosome and the Ski complex, which targets RNA transcripts to the exosome for processing and degradation in the cytoplasm. To explore the functional interactions between the RNA exosome and Nab2, we employed RNA-seq analysis to identify the transcripts most impacted by overexpression of these exosome cofactors in nab2 mutant cells. This analysis revealed that many transcripts show small changes in steady-state levels, consistent with a global role of Nab2 in modulating transcript stability. This study uncovers functional interactions between the RNA exosome and Nab2 in both the nucleus and the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

Section: Specific Rna Exosome Cofactors Suppress the Growth Defect Of...mentioning

confidence: 99%

The RNA binding protein Nab2 genetically interacts with multiple RNA exosome cofactors to regulate target RNAs

Kinney

Mills-Lujan

Fasken

et al. 2022

Preprint

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“…TRAMP allegedly targets anomalous or less steady tRNA by polyadenylating the 3′ end to furnish a single-stranded RNA extension that is long enough to facilitate the engagement of the Mtr4 helicase 35 . Das et al 36 found that exoribonuclease activities of Rrp6-associated RNA exosomes protected unfluctuating RNAs from TRAMP-mediated polyadenylation and degradation, whereas the catalytic activity of the exosome-TRAMP complex contributed to substrate distinction and degradation of less steady RNAs.…”

Section: Ribosome Quality Control Systemmentioning

confidence: 99%

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases

Zhao¹,

Yao²,

Zhang³

et al. 2022

Int. J. Biol. Sci.

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Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.

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“…Further catalytic activity is provided to the exosome by the RNase D-like 3 0 -5 0 exoribonuclease yRrp6/hEXOSC10 and its cofactors yRrp47/hC1D and yMpp6/hMPP6 (Briggs et al, 1998;Falk et al, 2017;Milligan et al, 2008;Mitchell et al, 2003;Schilders et al, 2007;Schuch et al, 2014;Wasmuth et al, 2014Wasmuth et al, , 2017Weick et al, 2018). yRrp6/hEXOSC10 possess distributive 3 0 -5 0 exoribonucleolytic activity employed to degrade substrates that do not pass through the channel of the complex (Das et al, 2021;Januszyk et al, 2011;Makino et al, 2015).…”

Section: The Rna Exosomementioning

confidence: 99%

Caught in the act—Visualizing ribonucleases during eukaryotic ribosome assembly

Schneider

Bohnsack

2022

WIREs RNA

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Ribosomes are essential macromolecular machines responsible for translating the genetic information encoded in mRNAs into proteins. Ribosomes are composed of ribosomal RNAs and proteins (rRNAs and RPs) and the rRNAs fulfill both catalytic and architectural functions. Excision of the mature eukaryotic rRNAs from their precursor transcript is achieved through a complex series of endoribonucleolytic cleavages and exoribonucleolytic processing steps that are precisely coordinated with other aspects of ribosome assembly. Many ribonucleases involved in pre-rRNA processing have been identified and pre-rRNA processing pathways are relatively well defined. However, momentous advances in cryo-electron microscopy have recently enabled structural snapshots of various pre-ribosomal particles from budding yeast (Saccharomyces cerevisiae) and human cells to be captured and, excitingly, these structures not only allow pre-rRNAs to be observed before and after cleavage events, but also enable ribonucleases to be visualized on their target RNAs. These structural views of pre-rRNA processing in action allow a new layer of understanding of rRNA maturation and how it is coordinated with other aspects of ribosome assembly. They illuminate mechanisms of target recognition by the diverse ribonucleases involved and reveal how the cleavage/processing activities of these enzymes are regulated. In this review, we discuss the new insights into pre-rRNA processing gained by structural analyses and the growing understanding of the mechanisms of ribonuclease regulation.

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Substrate discrimination and quality control require each catalytic activity of TRAMP and the nuclear RNA exosome

Cited by 9 publications

References 84 publications

The RNA binding protein Nab2 genetically interacts with multiple RNA exosome cofactors to regulate target RNAs

The RNA binding protein Nab2 genetically interacts with multiple RNA exosome cofactors to regulate target RNAs

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases

Caught in the act—Visualizing ribonucleases during eukaryotic ribosome assembly

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