Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns
Abstract Vertebrate genomes contain major (>99.5%) and minor (
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| Veröffentlicht in: | Nucleic acids research 2021-04, Vol.49 (6), p.3524-3545 |
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| creator | Olthof, Anouk M White, Alisa K Mieruszynski, Stephen Doggett, Karen Lee, Madisen F Chakroun, Almahdi Abdel Aleem, Alice K Rousseau, Justine Magnani, Cinzia Roifman, Chaim M Campeau, Philippe M Heath, Joan K Kanadia, Rahul N |
| description | Abstract
Vertebrate genomes contain major (>99.5%) and minor ( |
| doi_str_mv | 10.1093/nar/gkab118 |
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Vertebrate genomes contain major (>99.5%) and minor (<0.5%) introns that are spliced by the major and minor spliceosomes, respectively. Major intron splicing follows the exon-definition model, whereby major spliceosome components first assemble across exons. However, since most genes with minor introns predominately consist of major introns, formation of exon-definition complexes in these genes would require interaction between the major and minor spliceosomes. Here, we report that minor spliceosome protein U11-59K binds to the major spliceosome U2AF complex, thereby supporting a model in which the minor spliceosome interacts with the major spliceosome across an exon to regulate the splicing of minor introns. Inhibition of minor spliceosome snRNAs and U11-59K disrupted exon-bridging interactions, leading to exon skipping by the major spliceosome. The resulting aberrant isoforms contained a premature stop codon, yet were not subjected to nonsense-mediated decay, but rather bound to polysomes. Importantly, we detected elevated levels of these alternatively spliced transcripts in individuals with minor spliceosome-related diseases such as Roifman syndrome, Lowry–Wood syndrome and early-onset cerebellar ataxia. In all, we report that the minor spliceosome informs splicing by the major spliceosome through exon-definition interactions and show that minor spliceosome inhibition results in aberrant alternative splicing in disease.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab118</identifier><identifier>PMID: 33660780</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Alternative Splicing ; Animals ; Apoptosis Regulatory Proteins - metabolism ; Cardiomyopathies - genetics ; Cells, Cultured ; Cerebellar Ataxia - genetics ; Exons ; Growth Disorders - genetics ; Humans ; Intellectual Disability - genetics ; Introns ; Mental Retardation, X-Linked - genetics ; Mice ; Microcephaly - genetics ; Nonsense Mediated mRNA Decay ; Osteochondrodysplasias - genetics ; Polyribosomes - metabolism ; Primary Immunodeficiency Diseases - genetics ; Retinal Diseases - genetics ; RNA and RNA-protein complexes ; RNA, Small Nuclear - antagonists & inhibitors ; Spliceosomes - metabolism ; Transcription Factors - metabolism</subject><ispartof>Nucleic acids research, 2021-04, Vol.49 (6), p.3524-3545</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-3ee15a4b23aafbb7028cbe4bf5e3f6ea6cb1142ad9d47cb96b43d293445458613</citedby><cites>FETCH-LOGICAL-c412t-3ee15a4b23aafbb7028cbe4bf5e3f6ea6cb1142ad9d47cb96b43d293445458613</cites><orcidid>0000-0001-7197-912X ; 0000-0001-9713-7107</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/PMC8034651/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034651/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33660780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Olthof, Anouk M</creatorcontrib><creatorcontrib>White, Alisa K</creatorcontrib><creatorcontrib>Mieruszynski, Stephen</creatorcontrib><creatorcontrib>Doggett, Karen</creatorcontrib><creatorcontrib>Lee, Madisen F</creatorcontrib><creatorcontrib>Chakroun, Almahdi</creatorcontrib><creatorcontrib>Abdel Aleem, Alice K</creatorcontrib><creatorcontrib>Rousseau, Justine</creatorcontrib><creatorcontrib>Magnani, Cinzia</creatorcontrib><creatorcontrib>Roifman, Chaim M</creatorcontrib><creatorcontrib>Campeau, Philippe M</creatorcontrib><creatorcontrib>Heath, Joan K</creatorcontrib><creatorcontrib>Kanadia, Rahul N</creatorcontrib><title>Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Vertebrate genomes contain major (>99.5%) and minor (<0.5%) introns that are spliced by the major and minor spliceosomes, respectively. Major intron splicing follows the exon-definition model, whereby major spliceosome components first assemble across exons. However, since most genes with minor introns predominately consist of major introns, formation of exon-definition complexes in these genes would require interaction between the major and minor spliceosomes. Here, we report that minor spliceosome protein U11-59K binds to the major spliceosome U2AF complex, thereby supporting a model in which the minor spliceosome interacts with the major spliceosome across an exon to regulate the splicing of minor introns. Inhibition of minor spliceosome snRNAs and U11-59K disrupted exon-bridging interactions, leading to exon skipping by the major spliceosome. The resulting aberrant isoforms contained a premature stop codon, yet were not subjected to nonsense-mediated decay, but rather bound to polysomes. Importantly, we detected elevated levels of these alternatively spliced transcripts in individuals with minor spliceosome-related diseases such as Roifman syndrome, Lowry–Wood syndrome and early-onset cerebellar ataxia. In all, we report that the minor spliceosome informs splicing by the major spliceosome through exon-definition interactions and show that minor spliceosome inhibition results in aberrant alternative splicing in disease.</description><subject>Alternative Splicing</subject><subject>Animals</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Cardiomyopathies - genetics</subject><subject>Cells, Cultured</subject><subject>Cerebellar Ataxia - genetics</subject><subject>Exons</subject><subject>Growth Disorders - genetics</subject><subject>Humans</subject><subject>Intellectual Disability - genetics</subject><subject>Introns</subject><subject>Mental Retardation, X-Linked - genetics</subject><subject>Mice</subject><subject>Microcephaly - genetics</subject><subject>Nonsense Mediated mRNA Decay</subject><subject>Osteochondrodysplasias - genetics</subject><subject>Polyribosomes - metabolism</subject><subject>Primary Immunodeficiency Diseases - genetics</subject><subject>Retinal Diseases - genetics</subject><subject>RNA and RNA-protein complexes</subject><subject>RNA, Small Nuclear - antagonists & inhibitors</subject><subject>Spliceosomes - metabolism</subject><subject>Transcription Factors - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAURa0KRKctK_bIK4SEQu3YcZINUlUoIFViQ9fWs_MydUnsYCdT-AG-G4eZVrBhZUvvvHMtX0JecPaWs1ace4jn229gOG-OyIYLVRayVeUTsmGCVQVnsjkmJyndMcYlr-QzciyEUqxu2Ib8eu9SXKbZBU9DT_FH8IWJrts6v6XOzxjBrsNEDc73iJ7Ot0hH50Ok4Ds6wl2-pWlwFkMKIyYaMS3DnPI2hSELPMxuh3tmtUIMy7r5x5EjYrafkac9DAmfH85TcnP14evlp-L6y8fPlxfXhZW8nAuByCuQphQAvTE1KxtrUJq-QtErBGXzL8gSuraTtTWtMlJ0ZSukrGTVKC5Oybu9d1rMiJ3FHA-DnqIbIf7UAZz-d-Ldrd6GnW6YkKpaBa8Pghi-L5hmPbpkcRjAY1iSLmVbs7aWTZPRN3vUxpBSxP4xhjO9Nqdzc_rQXKZf_v2yR_ahqgy82gNhmf5r-g0GUKhA</recordid><startdate>20210406</startdate><enddate>20210406</enddate><creator>Olthof, Anouk M</creator><creator>White, Alisa K</creator><creator>Mieruszynski, Stephen</creator><creator>Doggett, Karen</creator><creator>Lee, Madisen F</creator><creator>Chakroun, Almahdi</creator><creator>Abdel Aleem, Alice K</creator><creator>Rousseau, Justine</creator><creator>Magnani, Cinzia</creator><creator>Roifman, Chaim M</creator><creator>Campeau, Philippe M</creator><creator>Heath, Joan K</creator><creator>Kanadia, Rahul N</creator><general>Oxford University Press</general><scope>TOX</scope><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7197-912X</orcidid><orcidid>https://orcid.org/0000-0001-9713-7107</orcidid></search><sort><creationdate>20210406</creationdate><title>Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns</title><author>Olthof, Anouk M ; White, Alisa K ; Mieruszynski, Stephen ; Doggett, Karen ; Lee, Madisen F ; Chakroun, Almahdi ; Abdel Aleem, Alice K ; Rousseau, Justine ; Magnani, Cinzia ; Roifman, Chaim M ; Campeau, Philippe M ; Heath, Joan K ; Kanadia, Rahul N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-3ee15a4b23aafbb7028cbe4bf5e3f6ea6cb1142ad9d47cb96b43d293445458613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alternative Splicing</topic><topic>Animals</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Cardiomyopathies - genetics</topic><topic>Cells, Cultured</topic><topic>Cerebellar Ataxia - genetics</topic><topic>Exons</topic><topic>Growth Disorders - genetics</topic><topic>Humans</topic><topic>Intellectual Disability - genetics</topic><topic>Introns</topic><topic>Mental Retardation, X-Linked - genetics</topic><topic>Mice</topic><topic>Microcephaly - genetics</topic><topic>Nonsense Mediated mRNA Decay</topic><topic>Osteochondrodysplasias - genetics</topic><topic>Polyribosomes - metabolism</topic><topic>Primary Immunodeficiency Diseases - genetics</topic><topic>Retinal Diseases - genetics</topic><topic>RNA and RNA-protein complexes</topic><topic>RNA, Small Nuclear - antagonists & inhibitors</topic><topic>Spliceosomes - metabolism</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Olthof, Anouk M</creatorcontrib><creatorcontrib>White, Alisa K</creatorcontrib><creatorcontrib>Mieruszynski, Stephen</creatorcontrib><creatorcontrib>Doggett, Karen</creatorcontrib><creatorcontrib>Lee, Madisen F</creatorcontrib><creatorcontrib>Chakroun, Almahdi</creatorcontrib><creatorcontrib>Abdel Aleem, Alice K</creatorcontrib><creatorcontrib>Rousseau, Justine</creatorcontrib><creatorcontrib>Magnani, Cinzia</creatorcontrib><creatorcontrib>Roifman, Chaim M</creatorcontrib><creatorcontrib>Campeau, Philippe M</creatorcontrib><creatorcontrib>Heath, Joan K</creatorcontrib><creatorcontrib>Kanadia, Rahul N</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Olthof, Anouk M</au><au>White, Alisa K</au><au>Mieruszynski, Stephen</au><au>Doggett, Karen</au><au>Lee, Madisen F</au><au>Chakroun, Almahdi</au><au>Abdel Aleem, Alice K</au><au>Rousseau, Justine</au><au>Magnani, Cinzia</au><au>Roifman, Chaim M</au><au>Campeau, Philippe M</au><au>Heath, Joan K</au><au>Kanadia, Rahul N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-04-06</date><risdate>2021</risdate><volume>49</volume><issue>6</issue><spage>3524</spage><epage>3545</epage><pages>3524-3545</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Vertebrate genomes contain major (>99.5%) and minor (<0.5%) introns that are spliced by the major and minor spliceosomes, respectively. Major intron splicing follows the exon-definition model, whereby major spliceosome components first assemble across exons. However, since most genes with minor introns predominately consist of major introns, formation of exon-definition complexes in these genes would require interaction between the major and minor spliceosomes. Here, we report that minor spliceosome protein U11-59K binds to the major spliceosome U2AF complex, thereby supporting a model in which the minor spliceosome interacts with the major spliceosome across an exon to regulate the splicing of minor introns. Inhibition of minor spliceosome snRNAs and U11-59K disrupted exon-bridging interactions, leading to exon skipping by the major spliceosome. The resulting aberrant isoforms contained a premature stop codon, yet were not subjected to nonsense-mediated decay, but rather bound to polysomes. Importantly, we detected elevated levels of these alternatively spliced transcripts in individuals with minor spliceosome-related diseases such as Roifman syndrome, Lowry–Wood syndrome and early-onset cerebellar ataxia. In all, we report that the minor spliceosome informs splicing by the major spliceosome through exon-definition interactions and show that minor spliceosome inhibition results in aberrant alternative splicing in disease.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33660780</pmid><doi>10.1093/nar/gkab118</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0001-7197-912X</orcidid><orcidid>https://orcid.org/0000-0001-9713-7107</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Oxford Journals Open Access Collection; MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alternative Splicing Animals Apoptosis Regulatory Proteins - metabolism Cardiomyopathies - genetics Cells, Cultured Cerebellar Ataxia - genetics Exons Growth Disorders - genetics Humans Intellectual Disability - genetics Introns Mental Retardation, X-Linked - genetics Mice Microcephaly - genetics Nonsense Mediated mRNA Decay Osteochondrodysplasias - genetics Polyribosomes - metabolism Primary Immunodeficiency Diseases - genetics Retinal Diseases - genetics RNA and RNA-protein complexes RNA, Small Nuclear - antagonists & inhibitors Spliceosomes - metabolism Transcription Factors - metabolism |
| title | Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns |
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