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Aberrant transcripts include mRNAs with a premature termination codon (PTC), targeted by the nonsense-mediated decay (NMD) pathway, and mRNAs lacking a termination codon, targeted by the nonstop decay (NSD) pathway. The eukaryotic exosome, a ribonucleolytic complex, plays a crucial role in mRNA processing and turnover through its catalytic subunits PM\/Scl100 (Rrp6 in yeast), DIS3 (Rrp44 in yeast), and DIS3L1. Additionally, eukaryotic cells have other ribonucleases, such as SMG6 and XRN1, that participate in RNA surveillance. However, the specific pathways through which ribonucleases recognize and degrade mRNAs remain elusive. In this study, we characterized the involvement of human ribonucleases, both nuclear and cytoplasmic, in the mRNA surveillance mechanisms of NMD and NSD. We performed knockdowns of SMG6, PM\/Scl100, XRN1, DIS3, and DIS3L1, analyzing the resulting changes in mRNA levels of selected natural NMD targets by RT-qPCR. Additionally, we examined the levels of different human \u03b2-globin variants under the same conditions: wild-type, NMD-resistant, NMD-sensitive, and NSD-sensitive. Our results demonstrate that all the studied ribonucleases are involved in the decay of certain endogenous NMD targets. Furthermore, we observed that the ribonucleases SMG6 and DIS3 contribute to the degradation of all \u03b2-globin variants, with an exception for \u03b2NS in the former case. This is also the case for PM\/Scl100, which affects all \u03b2-globin variants except the NMD-sensitive variants. In contrast, DIS3L1 and XRN1 show specificity for \u03b2-globin WT and NMD-resistant variants. These findings suggest that eukaryotic ribonucleases are target-specific rather than pathway-specific. In addition, our data suggest that ribonucleases play broader roles in mRNA surveillance and degradation mechanisms beyond just NMD and NSD.<\/jats:p>","DOI":"10.3390\/genes15101308","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T08:16:42Z","timestamp":1728548202000},"page":"1308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Comparative Overview of the Role of Human Ribonucleases in Nonsense-Mediated mRNA Decay"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-9965","authenticated-orcid":false,"given":"Paulo J.","family":"da Costa","sequence":"first","affiliation":[{"name":"Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3727-2096","authenticated-orcid":false,"given":"Juliane","family":"Menezes","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4840-7195","authenticated-orcid":false,"given":"Raquel","family":"Guedes","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"given":"Filipa P.","family":"Reis","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"given":"Alexandre","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0458-1036","authenticated-orcid":false,"given":"Margarida","family":"Saramago","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-7474","authenticated-orcid":false,"given":"Sandra C.","family":"Viegas","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1934-9301","authenticated-orcid":false,"given":"Cec\u00edlia M.","family":"Arraiano","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5061-5287","authenticated-orcid":false,"given":"Lu\u00edsa","family":"Rom\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal"},{"name":"BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.tig.2008.08.010","article-title":"Introducing sense into nonsense in treatments of human genetic diseases","volume":"24","author":"Linde","year":"2008","journal-title":"Trends Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/BJ20100699","article-title":"NMD: RNA biology meets human genetic medicine","volume":"430","author":"Bhuvanagiri","year":"2010","journal-title":"Biochem. 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