{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T08:40:33Z","timestamp":1771231233267,"version":"3.50.1"},"reference-count":37,"publisher":"Portland Press Ltd.","issue":"12","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":391,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,6,29]]},"abstract":"<jats:p>DIS3 (defective in sister chromatid joining) is the catalytic subunit of the exosome, a protein complex involved in the 3\u2032\u20135\u2032 degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two protein-coding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN (PilT N-terminal) domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is missing a segment with conserved amino acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 and the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared with isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared with isoform 2, whereas acute myeloid leukaemia and chronic myelomonocytic leukaemia patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Taken together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers.<\/jats:p>","DOI":"10.1042\/bcj20170962","type":"journal-article","created":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T16:40:13Z","timestamp":1527266413000},"page":"2091-2105","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers"],"prefix":"10.1042","volume":"475","author":[{"given":"Sophie R.","family":"Robinson","sequence":"first","affiliation":[{"name":"Medical Research Building, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra C.","family":"Viegas","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rute G.","family":"Matos","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Domingues","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisa","family":"Bedir","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen J.S.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Medical Research Building, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Chevassut","sequence":"additional","affiliation":[{"name":"Medical Research Building, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-8273","authenticated-orcid":false,"given":"Antony W.","family":"Oliver","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia M.","family":"Arraiano","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1863-3258","authenticated-orcid":false,"given":"Sarah F.","family":"Newbury","sequence":"additional","affiliation":[{"name":"Medical Research Building, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,6,29]]},"reference":[{"key":"2021112216523927100_BCJ-2017-0962C1","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1002\/wrna.1180","article-title":"The RNase II\/RNB family of exoribonucleases: putting the \u2018Dis\u2019 in disease","volume":"4","author":"Reis","year":"2013","journal-title":"Wiley Interdiscip. 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