Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes
Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous...
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creator | Lykke-Andersen, Søren Chen, Yun Ardal, Britt R Lilje, Berit Waage, Johannes Sandelin, Albin Jensen, Torben Heick |
description | Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 5'-3' decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD. |
doi_str_mv | 10.1101/gad.246538.114 |
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While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 5'-3' decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.246538.114</identifier><identifier>PMID: 25403180</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Endonucleases - metabolism ; HEK293 Cells ; Humans ; Nonsense Mediated mRNA Decay - genetics ; Nonsense Mediated mRNA Decay - physiology ; Protein Isoforms ; Research Paper ; RNA Splicing ; RNA, Small Nucleolar - metabolism ; Telomerase - genetics ; Telomerase - metabolism</subject><ispartof>Genes & development, 2014-11, Vol.28 (22), p.2498-2517</ispartof><rights>2014 Lykke-Andersen et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c559t-64a64da59d5538b8ef0e329dc63646ce1f804ed546705f7ba74983b7d4605bd73</citedby><cites>FETCH-LOGICAL-c559t-64a64da59d5538b8ef0e329dc63646ce1f804ed546705f7ba74983b7d4605bd73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233243/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233243/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25403180$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lykke-Andersen, Søren</creatorcontrib><creatorcontrib>Chen, Yun</creatorcontrib><creatorcontrib>Ardal, Britt R</creatorcontrib><creatorcontrib>Lilje, Berit</creatorcontrib><creatorcontrib>Waage, Johannes</creatorcontrib><creatorcontrib>Sandelin, Albin</creatorcontrib><creatorcontrib>Jensen, Torben Heick</creatorcontrib><title>Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 5'-3' decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD.</description><subject>Endonucleases - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Nonsense Mediated mRNA Decay - genetics</subject><subject>Nonsense Mediated mRNA Decay - physiology</subject><subject>Protein Isoforms</subject><subject>Research Paper</subject><subject>RNA Splicing</subject><subject>RNA, Small Nucleolar - metabolism</subject><subject>Telomerase - genetics</subject><subject>Telomerase - metabolism</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUcFq3DAQFaEh2W5y7bHo2Iu3kiWN7EshhLYphARCchayNN6oeKXUslv899WySWhvgYFhZt57zOMR8oGzDeeMf95av6klKNGUWR6RFVeyrZTU-h1ZsaZlVSugPSXvc_7JGAMGcEJOayWZ4A1bEXc172ykMcWMpaod-mAn9PTu5oJ6dHahIYZpv8v0T_A4LLRbKEaf4uwGTMOSQ6Y2ejrZcYtTpjmmPfkx5YluMWI-I8e9HTKeP_c1efj29f7yqrq-_f7j8uK6ckq1UwXSgvRWtV4VO12DPUNRt96BAAkOed8wiV5J0Ez1urNato3otJfAVOe1WJMvB92nuSs-HMZptIN5GsPOjotJNpj_LzE8mm36bWQtRC1FEfj0LDCmXzPmyexCdjgMNmKas-GgQSjd1PoN0Bo4gCzSa7I5QN2Ych6xf_2IM7MP0ZQQzSHEMstC-Pivj1f4S2riL2GImU0</recordid><startdate>20141115</startdate><enddate>20141115</enddate><creator>Lykke-Andersen, Søren</creator><creator>Chen, Yun</creator><creator>Ardal, Britt R</creator><creator>Lilje, Berit</creator><creator>Waage, Johannes</creator><creator>Sandelin, Albin</creator><creator>Jensen, Torben Heick</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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20141115</creationdate><title>Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes</title><author>Lykke-Andersen, Søren ; Chen, Yun ; Ardal, Britt R ; Lilje, Berit ; Waage, Johannes ; Sandelin, Albin ; Jensen, Torben Heick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c559t-64a64da59d5538b8ef0e329dc63646ce1f804ed546705f7ba74983b7d4605bd73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Endonucleases - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Nonsense Mediated mRNA Decay - genetics</topic><topic>Nonsense Mediated mRNA Decay - physiology</topic><topic>Protein Isoforms</topic><topic>Research Paper</topic><topic>RNA Splicing</topic><topic>RNA, Small Nucleolar - metabolism</topic><topic>Telomerase - genetics</topic><topic>Telomerase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lykke-Andersen, Søren</creatorcontrib><creatorcontrib>Chen, Yun</creatorcontrib><creatorcontrib>Ardal, Britt R</creatorcontrib><creatorcontrib>Lilje, Berit</creatorcontrib><creatorcontrib>Waage, Johannes</creatorcontrib><creatorcontrib>Sandelin, Albin</creatorcontrib><creatorcontrib>Jensen, Torben Heick</creatorcontrib><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>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lykke-Andersen, Søren</au><au>Chen, Yun</au><au>Ardal, Britt R</au><au>Lilje, Berit</au><au>Waage, Johannes</au><au>Sandelin, Albin</au><au>Jensen, Torben Heick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2014-11-15</date><risdate>2014</risdate><volume>28</volume><issue>22</issue><spage>2498</spage><epage>2517</epage><pages>2498-2517</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 5'-3' decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>25403180</pmid><doi>10.1101/gad.246538.114</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Endonucleases - metabolism HEK293 Cells Humans Nonsense Mediated mRNA Decay - genetics Nonsense Mediated mRNA Decay - physiology Protein Isoforms Research Paper RNA Splicing RNA, Small Nucleolar - metabolism Telomerase - genetics Telomerase - metabolism |
title | Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes |
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