ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?
| dc.contributor.author | Dinan, Adam M. | |
| dc.contributor.author | Atkins, John F. | |
| dc.contributor.author | Firth, Andrew E. | |
| dc.contributor.funder | Science Foundation Ireland | |
| dc.contributor.funder | Horizon 2020 | |
| dc.contributor.funder | Wellcome Trust | |
| dc.date.accessioned | 2017-12-08T13:33:45Z | |
| dc.date.available | 2017-12-08T13:33:45Z | |
| dc.date.issued | 2017-10-16 | |
| 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.description.status | Peer reviewed | en |
| dc.description.version | Published Version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.articleid | 24 | |
| 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.doi | 10.1186/s13062-017-0195-0 | |
| dc.identifier.endpage | 16 | |
| dc.identifier.issn | 1745-6150 | |
| dc.identifier.issued | 24 | |
| dc.identifier.journaltitle | Biology Direct | en |
| dc.identifier.startpage | 1 | |
| dc.identifier.uri | https://hdl.handle.net/10468/5145 | |
| dc.identifier.volume | 12 | |
| dc.language.iso | en | en |
| dc.publisher | BioMed Central | en |
| 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 | |
| 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 |