A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex
RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a cataly...
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creator | Sterrett, Maria C Enyenihi, Liz Leung, Sara W Hess, Laurie Strassler, Sarah E Farchi, Daniela Lee, Richard S Withers, Elise S Kremsky, Isaac Baker, Richard E Basrai, Munira A van Hoof, Ambro Fasken, Milo B Corbett, Anita H |
description | RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene
cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (
hort stature,
earing loss,
etinitis pigmentosa, and distinctive
acies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic
missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous
gene
The resulting
mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in
cells that model
p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in
impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies. |
doi_str_mv | 10.1261/rna.078618.120 |
format | Article |
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cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (
hort stature,
earing loss,
etinitis pigmentosa, and distinctive
acies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic
missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous
gene
The resulting
mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in
cells that model
p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in
impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.</description><identifier>ISSN: 1355-8382</identifier><identifier>EISSN: 1469-9001</identifier><identifier>DOI: 10.1261/rna.078618.120</identifier><identifier>PMID: 34162742</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Amino Acid Sequence ; Amino Acid Substitution ; Amino acids ; Aspartic Acid - chemistry ; Aspartic Acid - metabolism ; Cofactors ; Dwarfism - enzymology ; Dwarfism - genetics ; Dwarfism - pathology ; Exoribonucleases - chemistry ; Exoribonucleases - genetics ; Exoribonucleases - metabolism ; Exosome Multienzyme Ribonuclease Complex - chemistry ; Exosome Multienzyme Ribonuclease Complex - genetics ; Exosome Multienzyme Ribonuclease Complex - metabolism ; Facies ; Gene Expression ; Genes ; Genetic analysis ; Glycine - chemistry ; Glycine - metabolism ; Hearing loss ; Hearing Loss - enzymology ; Hearing Loss - genetics ; Hearing Loss - pathology ; Humans ; Hypoplasia ; Missense mutation ; Models, Biological ; Models, Molecular ; Mutation ; Mutation, Missense ; Protein Conformation ; Retinitis ; Retinitis pigmentosa ; Retinitis Pigmentosa - enzymology ; Retinitis Pigmentosa - genetics ; Retinitis Pigmentosa - pathology ; Ribonucleic acid ; RNA ; RNA, Fungal - chemistry ; RNA, Fungal - genetics ; RNA, Fungal - metabolism ; RNA-Binding Proteins - chemistry ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Saccharomyces cerevisiae - enzymology ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae Proteins - chemistry ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Sequence Homology, Amino Acid ; Syndrome ; Transcriptomics</subject><ispartof>RNA (Cambridge), 2021-09, Vol.27 (9), p.1046-1067</ispartof><rights>2021 Sterrett et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.</rights><rights>Copyright Cold Spring Harbor Laboratory Press Sep 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-1441aa2b6e0e744a6bf0c4a85913393d11f0d27fb3fb00a06810e8c29cea9fec3</citedby><cites>FETCH-LOGICAL-c418t-1441aa2b6e0e744a6bf0c4a85913393d11f0d27fb3fb00a06810e8c29cea9fec3</cites><orcidid>0000-0002-0346-181X ; 0000-0002-9772-2426 ; 0000-0002-0461-6895</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370739/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370739/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34162742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sterrett, Maria C</creatorcontrib><creatorcontrib>Enyenihi, Liz</creatorcontrib><creatorcontrib>Leung, Sara W</creatorcontrib><creatorcontrib>Hess, Laurie</creatorcontrib><creatorcontrib>Strassler, Sarah E</creatorcontrib><creatorcontrib>Farchi, Daniela</creatorcontrib><creatorcontrib>Lee, Richard S</creatorcontrib><creatorcontrib>Withers, Elise S</creatorcontrib><creatorcontrib>Kremsky, Isaac</creatorcontrib><creatorcontrib>Baker, Richard E</creatorcontrib><creatorcontrib>Basrai, Munira A</creatorcontrib><creatorcontrib>van Hoof, Ambro</creatorcontrib><creatorcontrib>Fasken, Milo B</creatorcontrib><creatorcontrib>Corbett, Anita H</creatorcontrib><title>A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex</title><title>RNA (Cambridge)</title><addtitle>RNA</addtitle><description>RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene
cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (
hort stature,
earing loss,
etinitis pigmentosa, and distinctive
acies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic
missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous
gene
The resulting
mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in
cells that model
p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in
impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.</description><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Amino acids</subject><subject>Aspartic Acid - chemistry</subject><subject>Aspartic Acid - metabolism</subject><subject>Cofactors</subject><subject>Dwarfism - enzymology</subject><subject>Dwarfism - genetics</subject><subject>Dwarfism - pathology</subject><subject>Exoribonucleases - chemistry</subject><subject>Exoribonucleases - genetics</subject><subject>Exoribonucleases - metabolism</subject><subject>Exosome Multienzyme Ribonuclease Complex - chemistry</subject><subject>Exosome Multienzyme Ribonuclease Complex - genetics</subject><subject>Exosome Multienzyme Ribonuclease Complex - metabolism</subject><subject>Facies</subject><subject>Gene Expression</subject><subject>Genes</subject><subject>Genetic analysis</subject><subject>Glycine - chemistry</subject><subject>Glycine - metabolism</subject><subject>Hearing loss</subject><subject>Hearing Loss - enzymology</subject><subject>Hearing Loss - genetics</subject><subject>Hearing Loss - pathology</subject><subject>Humans</subject><subject>Hypoplasia</subject><subject>Missense mutation</subject><subject>Models, Biological</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Protein Conformation</subject><subject>Retinitis</subject><subject>Retinitis pigmentosa</subject><subject>Retinitis Pigmentosa - enzymology</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Retinitis Pigmentosa - pathology</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Fungal - chemistry</subject><subject>RNA, Fungal - genetics</subject><subject>RNA, Fungal - metabolism</subject><subject>RNA-Binding Proteins - chemistry</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Saccharomyces cerevisiae - enzymology</subject><subject>Saccharomyces cerevisiae - genetics</subject><subject>Saccharomyces cerevisiae Proteins - chemistry</subject><subject>Saccharomyces cerevisiae Proteins - genetics</subject><subject>Saccharomyces cerevisiae Proteins - metabolism</subject><subject>Sequence Homology, Amino Acid</subject><subject>Syndrome</subject><subject>Transcriptomics</subject><issn>1355-8382</issn><issn>1469-9001</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUUtLxDAQDqL4WL16lIDnrpkk26YXYVnWB4iCD_AW0nTiVtpmbVpx_73RXUVP8_i--WaYj5BjYGPgKZx1rRmzTKWgYs22yD7INE9yxmA75mIySZRQfI8chPAamyLCu2RPSEh5Jvk-cVNaDGVZtS90hSb0tPEl1tT5ji6GxrS0rELsI22G3vSVbwOtWtovkM6f7x5mnFqzpGEohrbqqXffyP3tlOKHD75Ban2zrPHjkOw4Uwc82sQRebqYP86ukpu7y-vZ9CaxElSfgJRgDC9SZJhJadLCMSuNmuQgRC5KAMdKnrlCuIIxw1IFDJXluUWTO7RiRM7XusuhaLC02PadqfWyqxrTrbQ3lf6PtNVCv_h3rUTGsrhiRE43Ap1_GzD0-tUP8cl10HySAYgUMhlZ4zXLdj6EDt3vBmD6yxcdR_Tal1izOHDy965f-o8R4hPeNYnU</recordid><startdate>202109</startdate><enddate>202109</enddate><creator>Sterrett, Maria C</creator><creator>Enyenihi, Liz</creator><creator>Leung, Sara W</creator><creator>Hess, Laurie</creator><creator>Strassler, Sarah E</creator><creator>Farchi, Daniela</creator><creator>Lee, Richard S</creator><creator>Withers, Elise S</creator><creator>Kremsky, Isaac</creator><creator>Baker, Richard E</creator><creator>Basrai, Munira A</creator><creator>van Hoof, Ambro</creator><creator>Fasken, Milo B</creator><creator>Corbett, Anita H</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0346-181X</orcidid><orcidid>https://orcid.org/0000-0002-9772-2426</orcidid><orcidid>https://orcid.org/0000-0002-0461-6895</orcidid></search><sort><creationdate>202109</creationdate><title>A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex</title><author>Sterrett, Maria C ; Enyenihi, Liz ; Leung, Sara W ; Hess, Laurie ; Strassler, Sarah E ; Farchi, Daniela ; Lee, Richard S ; Withers, Elise S ; Kremsky, Isaac ; Baker, Richard E ; Basrai, Munira A ; van Hoof, Ambro ; Fasken, Milo B ; Corbett, Anita H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-1441aa2b6e0e744a6bf0c4a85913393d11f0d27fb3fb00a06810e8c29cea9fec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Amino acids</topic><topic>Aspartic Acid - chemistry</topic><topic>Aspartic Acid - metabolism</topic><topic>Cofactors</topic><topic>Dwarfism - enzymology</topic><topic>Dwarfism - genetics</topic><topic>Dwarfism - pathology</topic><topic>Exoribonucleases - chemistry</topic><topic>Exoribonucleases - genetics</topic><topic>Exoribonucleases - metabolism</topic><topic>Exosome Multienzyme Ribonuclease Complex - chemistry</topic><topic>Exosome Multienzyme Ribonuclease Complex - genetics</topic><topic>Exosome Multienzyme Ribonuclease Complex - metabolism</topic><topic>Facies</topic><topic>Gene Expression</topic><topic>Genes</topic><topic>Genetic analysis</topic><topic>Glycine - chemistry</topic><topic>Glycine - metabolism</topic><topic>Hearing loss</topic><topic>Hearing Loss - enzymology</topic><topic>Hearing Loss - genetics</topic><topic>Hearing Loss - pathology</topic><topic>Humans</topic><topic>Hypoplasia</topic><topic>Missense mutation</topic><topic>Models, Biological</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Protein Conformation</topic><topic>Retinitis</topic><topic>Retinitis pigmentosa</topic><topic>Retinitis Pigmentosa - enzymology</topic><topic>Retinitis Pigmentosa - genetics</topic><topic>Retinitis Pigmentosa - pathology</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Fungal - chemistry</topic><topic>RNA, Fungal - genetics</topic><topic>RNA, Fungal - metabolism</topic><topic>RNA-Binding Proteins - chemistry</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Saccharomyces cerevisiae - enzymology</topic><topic>Saccharomyces cerevisiae - genetics</topic><topic>Saccharomyces cerevisiae Proteins - chemistry</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Saccharomyces cerevisiae Proteins - metabolism</topic><topic>Sequence Homology, Amino Acid</topic><topic>Syndrome</topic><topic>Transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sterrett, Maria C</creatorcontrib><creatorcontrib>Enyenihi, Liz</creatorcontrib><creatorcontrib>Leung, Sara W</creatorcontrib><creatorcontrib>Hess, Laurie</creatorcontrib><creatorcontrib>Strassler, Sarah E</creatorcontrib><creatorcontrib>Farchi, Daniela</creatorcontrib><creatorcontrib>Lee, Richard S</creatorcontrib><creatorcontrib>Withers, Elise S</creatorcontrib><creatorcontrib>Kremsky, Isaac</creatorcontrib><creatorcontrib>Baker, Richard E</creatorcontrib><creatorcontrib>Basrai, Munira A</creatorcontrib><creatorcontrib>van Hoof, Ambro</creatorcontrib><creatorcontrib>Fasken, Milo B</creatorcontrib><creatorcontrib>Corbett, Anita H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>RNA (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sterrett, Maria C</au><au>Enyenihi, Liz</au><au>Leung, Sara W</au><au>Hess, Laurie</au><au>Strassler, Sarah E</au><au>Farchi, Daniela</au><au>Lee, Richard S</au><au>Withers, Elise S</au><au>Kremsky, Isaac</au><au>Baker, Richard E</au><au>Basrai, Munira A</au><au>van Hoof, Ambro</au><au>Fasken, Milo B</au><au>Corbett, Anita H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex</atitle><jtitle>RNA (Cambridge)</jtitle><addtitle>RNA</addtitle><date>2021-09</date><risdate>2021</risdate><volume>27</volume><issue>9</issue><spage>1046</spage><epage>1067</epage><pages>1046-1067</pages><issn>1355-8382</issn><eissn>1469-9001</eissn><abstract>RNA exosomopathies, a growing family of diseases, are linked to missense mutations in genes encoding structural subunits of the evolutionarily conserved, 10-subunit exoribonuclease complex, the RNA exosome. This complex consists of a three-subunit cap, a six-subunit, barrel-shaped core, and a catalytic base subunit. While a number of mutations in RNA exosome genes cause pontocerebellar hypoplasia, mutations in the cap subunit gene
cause an apparently distinct clinical presentation that has been defined as a novel syndrome SHRF (
hort stature,
earing loss,
etinitis pigmentosa, and distinctive
acies). We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by modeling pathogenic
missense mutations (p.Gly30Val and p.Gly198Asp) in the orthologous
gene
The resulting
mutant cells show defects in cell growth and RNA exosome function. Consistent with altered RNA exosome function, we detect significant transcriptomic changes in both coding and noncoding RNAs in
cells that model
p.Gly198Asp, suggesting defects in nuclear surveillance. Biochemical and genetic analyses suggest that the Rrp4 G226D variant subunit shows impaired interactions with key RNA exosome cofactors that modulate the function of the complex. These results provide the first in vivo evidence that pathogenic missense mutations present in
impair the function of the RNA exosome. This study also sets the stage to compare exosomopathy models to understand how defects in RNA exosome function underlie distinct pathologies.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>34162742</pmid><doi>10.1261/rna.078618.120</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0002-0346-181X</orcidid><orcidid>https://orcid.org/0000-0002-9772-2426</orcidid><orcidid>https://orcid.org/0000-0002-0461-6895</orcidid><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
subjects | Amino Acid Sequence Amino Acid Substitution Amino acids Aspartic Acid - chemistry Aspartic Acid - metabolism Cofactors Dwarfism - enzymology Dwarfism - genetics Dwarfism - pathology Exoribonucleases - chemistry Exoribonucleases - genetics Exoribonucleases - metabolism Exosome Multienzyme Ribonuclease Complex - chemistry Exosome Multienzyme Ribonuclease Complex - genetics Exosome Multienzyme Ribonuclease Complex - metabolism Facies Gene Expression Genes Genetic analysis Glycine - chemistry Glycine - metabolism Hearing loss Hearing Loss - enzymology Hearing Loss - genetics Hearing Loss - pathology Humans Hypoplasia Missense mutation Models, Biological Models, Molecular Mutation Mutation, Missense Protein Conformation Retinitis Retinitis pigmentosa Retinitis Pigmentosa - enzymology Retinitis Pigmentosa - genetics Retinitis Pigmentosa - pathology Ribonucleic acid RNA RNA, Fungal - chemistry RNA, Fungal - genetics RNA, Fungal - metabolism RNA-Binding Proteins - chemistry RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Saccharomyces cerevisiae - enzymology Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Sequence Homology, Amino Acid Syndrome Transcriptomics |
title | A budding yeast model for human disease mutations in the EXOSC2 cap subunit of the RNA exosome complex |
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