ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?

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dc.contributor.author Dinan, Adam M.
dc.contributor.author Atkins, John F.
dc.contributor.author Firth, Andrew E.
dc.date.accessioned 2017-12-08T13:33:45Z
dc.date.available 2017-12-08T13:33:45Z
dc.date.issued 2017-10-16
dc.identifier.citation Dinan, A. M., Atkins, J. F. and Firth, A. E. (2017) 'ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?', Biology Direct, 12, 24 (16pp). doi: 10.1186/s13062-017-0195-0 en
dc.identifier.volume 12
dc.identifier.issued 24
dc.identifier.startpage 1
dc.identifier.endpage 16
dc.identifier.issn 1745-6150
dc.identifier.uri http://hdl.handle.net/10468/5145
dc.identifier.doi 10.1186/s13062-017-0195-0
dc.description.abstract Background: Programmed ribosomal frameshifting (PRF) is a gene expression mechanism which enables the translation of two N-terminally coincident, C-terminally distinct protein products from a single mRNA. Many viruses utilize PRF to control or regulate gene expression, but very few phylogenetically conserved examples are known in vertebrate genes. Additional sex combs-like (ASXL) genes 1 and 2 encode important epigenetic and transcriptional regulatory proteins that control the expression of homeotic genes during key developmental stages. Here we describe an ~150-codon overlapping ORF (termed TF) in ASXL1 and ASXL2 that, with few exceptions, is conserved throughout vertebrates. Results: Conservation of the TF ORF, strong suppression of synonymous site variation in the overlap region, and the completely conserved presence of an EH[N/S]Y motif (a known binding site for Host Cell Factor-1, HCF-1, an epigenetic regulatory factor), all indicate that TF is a protein-coding sequence. A highly conserved UCC_UUU_CGU sequence (identical to the known site of +1 ribosomal frameshifting for influenza virus PA-X expression) occurs at the 5′ end of the region of enhanced synonymous site conservation in ASXL1. Similarly, a highly conserved RG_GUC_UCU sequence (identical to a known site of −2 ribosomal frameshifting for arterivirus nsp2TF expression) occurs at the 5′ end of the region of enhanced synonymous site conservation in ASXL2. Conclusions: Due to a lack of appropriate splice forms, or initiation sites, the most plausible mechanism for translation of the ASXL1 and 2 TF regions is ribosomal frameshifting, resulting in a transframe fusion of the N-terminal half of ASXL1 or 2 to the TF product, termed ASXL-TF. Truncation or frameshift mutants of ASXL are linked to myeloid malignancies and genetic diseases, such as Bohring-Opitz syndrome, likely at least in part as a result of gain-of-function or dominant-negative effects. Our hypothesis now indicates that these disease-associated mutant forms represent overexpressed defective versions of ASXL-TF. en
dc.description.sponsorship Wellcome Trust (088789; 106207) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher BioMed Central en
dc.relation.uri https://biologydirect.biomedcentral.com/articles/10.1186/s13062-017-0195-0
dc.rights © 2017, the Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. en
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject Ribosomal frameshifting en
dc.subject Translation en
dc.subject Protein synthesis en
dc.subject ASXL1 en
dc.subject ASXL2 en
dc.subject HCF-1 en
dc.subject BAP1 en
dc.subject Additional sex combs-like en
dc.subject Overlapping gene en
dc.title ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product? en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother John F. Atkins, Biochemistry, University College Cork , Cork, Ireland T: +353-21-490-3000. E: j.atkins@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Science Foundation Ireland
dc.contributor.funder Horizon 2020
dc.contributor.funder Wellcome Trust
dc.description.status Peer reviewed en
dc.identifier.journaltitle Biology Direct en
dc.internal.IRISemailaddress j.atkins@ucc.ie en
dc.identifier.articleid 24
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Investigator Programme/13/IA/1853/IE/Dynamic redefinition of codons: From antivirals to an essential micronutrient/
dc.relation.project info:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IP/1492/IE/Using ribosome profiling to study translation initiation/elongation and facilitate optimization of protein synthesis/
dc.relation.project info:eu-repo/grantAgreement/EC/H2020::ERC::ERC-COG/646891/EU/Systematic discovery of functional elements in RNA virus genomes: an Encyclopedia of RNA Virus Elements/ERVE


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© 2017, the Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Except where otherwise noted, this item's license is described as © 2017, the Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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