Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase

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

doi:10.7554/elife.29062

Cited by 53 publications

(81 citation statements)

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“…In particular, the nuclear Rrp47 cofactor interacts with Rrp6 via intertwined helices that form a composite surface, binding to Mtr4 of the TRAMP complex and other complexes and recruiting Mtr4 to the RNA exosome (Schuch et al 2014). Furthermore, the nuclear Mpp6 cofactor interacts with the Rrp40 cap subunit and can also recruit Mtr4 to the RNA exosome (Falk et al 2017;Wasmuth et al 2017). The cytoplasmic Ski7 cofactor interacts with the Csl4 cap subunit and two ring subunits, Mtr3 and Rrp43 (Kowalinski et al 2016).…”

Section: Comparisons and Potential Mechanisms Of Exosomelinked Diseasementioning

confidence: 99%

“…EXOSC2/3/8 variants could therefore potentially alter interactions with EXOSC10/Rrp6, C1D/Rrp47, hMPP6/Mpp6, or HBS1L3/ Ski7 to cause tissue-specific disease, if interactions of the human exosome cofactor orthologs with the human RNA exosome are conserved. As EXOSC10/Rrp6, C1D/Rrp47, and hMPP6/Mpp6 all facilitate recruitment of hMTR4/Mtr4 (Schilders et al 2007;Lubas et al 2011;Falk et al 2017;Wasmuth et al 2017) and Ski7 interacts with the Ski complex (Araki et al 2001;Wang et al 2005;Kowalinski et al 2016), EXOSC2/3/8 variants could also differentially impair interactions with the NEXT, TRAMP, and Ski complexes to cause disease. Certainly, the EXOSC2/3/8 subunits could also specifically interact with different, as-yet unidentified, tissue-specific exosome cofactors and therefore the EXOSC2/3/8 variants would only affect tissues that harbor a subunit-specific exosome cofactor.…”

Section: Comparisons and Potential Mechanisms Of Exosomelinked Diseasementioning

confidence: 99%

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The RNA exosome and RNA exosome-linked disease

Morton

Kuiper

Jones

et al. 2017

RNA

123

124

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The RNA exosome is an evolutionarily conserved, ribonuclease complex that is critical for both processing and degradation of a variety of RNAs. Cofactors that associate with the RNA exosome likely dictate substrate specificity for this complex. Recently, mutations in genes encoding both structural subunits of the RNA exosome and its cofactors have been linked to human disease. Mutations in the RNA exosome genes and cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are similar autosomal-recessive, neurodegenerative diseases. Mutations in the RNA exosome gene cause a distinct syndrome with various tissue-specific phenotypes including retinitis pigmentosa and mild intellectual disability. Mutations in genes that encode RNA exosome cofactors also cause tissue-specific diseases with complex phenotypes. How mutations in these genes give rise to distinct, tissue-specific diseases is not clear. In this review, we discuss the role of the RNA exosome complex and its cofactors in human disease, consider the amino acid changes that have been implicated in disease, and speculate on the mechanisms by which exosome gene mutations could underlie dysfunction and disease.

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Section: Comparisons and Potential Mechanisms Of Exosomelinked Diseasementioning

confidence: 99%

Section: Comparisons and Potential Mechanisms Of Exosomelinked Diseasementioning

confidence: 99%

The RNA exosome and RNA exosome-linked disease

Morton

Kuiper

Jones

et al. 2017

RNA

123

124

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“…First, amino acid substitutions could directly alter interactions with specific target RNAs. In budding yeast, the three cap subunits of the RNA exosome make direct contact with RNA [8,33], and the integrity of the S1/KH cap subunit ring is critical for the path of RNA to Rrp6, the nuclear catalytic subunit of the exosome [33].…”

Section: Discussionmentioning

confidence: 99%

“…A variety of cofactors associate with the RNA exosome to confer specificity for target RNAs and/or facilitate the unwinding of structured RNAs [34]. Indeed, structural studies show that the nuclear RNA exosome cofactor Mpp6 interacts with the Rrp40 cap subunit [33,36], and that an amino acid change in Rrp40 that models a change in PCH1b decreases the interaction of Mpp6 with the RNA exosome [36]. The idea that interactions with specific cofactors could be perturbed by the amino acid changes that occur in disease is attractive because altered interactions with cofactors in different tissues or cell types could explain the phenotypic variation Morton et al 14 observed for mutations within the same EXOSC gene or the different EXOSC subunit genes that are linked to distinct diseases.…”

Section: Discussionmentioning

confidence: 99%

“…As a first approach to consider how amino acid substitutions in EXOSC3 could impact the overall RNA exosome complex, we can take advantage of the availability of structures of this large macromolecular complex [8,9,43,45,46]. While there is no structure available of the Drosophila RNA exosome, the considerable evolutionary conservation illustrated in Fig 3B provides some context to consider how distinct amino acid changes in EXOSC3/Rrp40 could impair RNA exosome function.…”

Section: Discussionmentioning

confidence: 99%

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ADrosophilaModel of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons

Morton

Jalloh

Kim

et al. 2019

Preprint

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6Co-corresponding Authors Phone: 770-289-9986 (DJM) and Running title: Analysis of RNA exosome disease-linked substitutions in Drosophila EXOSC3 ortholog AbstractThe RNA exosome is an evolutionarily-conserved ribonuclease complex critically important for precise processing and/or complete degradation of a variety of cellular RNAs. The recent discovery that mutations in genes encoding structural RNA exosome subunits cause tissue-specific diseases makes defining the role of this complex within specific tissues critically important. Mutations in the RNA exosome component 3 (EXOSC3) gene cause Pontocerebellar Hypoplasia Type 1b (PCH1b), an autosomal recessive neurologic disorder. The majority of disease-linked mutations are missense mutations that alter evolutionarily-conserved regions of EXOSC3. The tissue-specific defects caused by these amino acid changes in EXOSC3 are challenging to understand based on current models of RNA exosome function with only limited analysis of the complex in any multicellular model in vivo. The goal of this study is to provide insight into how mutations in EXOSC3 impact the function of the RNA exosome. To assess the tissue-specific roles and requirements for the Drosophila ortholog of EXOSC3 termed Rrp40, we utilized tissue-specific RNAi drivers. Depletion of Rrp40 in different tissues reveals a general requirement for Rrp40 in the development of many tissues including the brain, but also highlight an agedependent requirement for Rrp40 in neurons. To assess the functional consequences of the specific amino acid substitutions in EXOSC3 that cause PCH1b, we used CRISPR/Cas9 gene editing technology to generate flies that model this RNA exosome-linked disease. These flies show reduced viability; however, the surviving animals exhibit a spectrum of behavioral and morphological phenotypes. RNA-seq analysis of these Drosophila Rrp40 mutants reveals increases in the steady-state levels of specific mRNAs and ncRNAs, some of which are central to neuronal function. In particular, Arc1 mRNA, which encodes a key regulator of synaptic plasticity, is increased in the Drosophila Rrp40 mutants. Taken together, this study defines a requirement for the RNA exosome in specific tissues/cell types and provides insight into how defects in RNA exosome function caused by specific amino acid substitutions that occur in PCH1b can contribute to neuronal dysfunction. Morton et al. 3 Author SummaryPontocerebellar Hypoplasia Type 1b (PCH1b) is a devastating genetic neurological disorder that preferentially affects specific regions of the brain. Typically, children born with PCH1b have structural defects in regions of the brain including those associated with key autonomic functions. Currently, there is no cure or treatment for the disease. PCH1b is caused by mutations in the RNA exosome component 3 (EXOSC3) gene, which encodes a structural component of the ubiquitous and essential multi-subunit RNA exosome complex.The RNA exosome is critical for both precise processing and turnover of multiple classes of RNAs. To el...

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Assembly of multicomponent machines inRNAmetabolism: A common theme inmRNAdecay pathways

Amorim

Chakrabarti

2021

WIREs RNA

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Multicomponent protein-RNA complexes comprising a ribonuclease and partner RNA helicase facilitate the turnover of mRNA in all domains of life. While these higher-order complexes provide an effective means of physically and functionally coupling the processes of RNA remodeling and decay, most ribonucleases and RNA helicases do not exhibit sequence specificity in RNA binding. This raises the question as to how these assemblies select substrates for processing and how the activities are orchestrated at the precise moment to ensure efficient decay. The answers to these apparent puzzles lie in the auxiliary components of the assemblies that might relay decay-triggering signals.Given their function within the assemblies, these components may be viewed as "sensors." The functions and mechanisms of action of the sensor components in various degradation complexes in bacteria and eukaryotes are highlighted here to discuss their roles in RNA decay processes.

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Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase

Cited by 53 publications

References 63 publications

The RNA exosome and RNA exosome-linked disease

The RNA exosome and RNA exosome-linked disease

ADrosophilaModel of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons

Assembly of multicomponent machines inRNAmetabolism: A common theme inmRNAdecay pathways

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