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dc.contributor.authorDinan, Adamen
dc.contributor.authorAtkins, John Fen
dc.contributor.authorFirth, Andrewen
dc.date.accessioned2018-05-31T09:49:31Z
dc.date.available2018-05-31T09:49:31Z
dc.date.issued2017-10-16en
dc.identifier.issn1745-6150
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276372
dc.description.abstractBackground: 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.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherBioMed Central
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAnimalsen
dc.subjectVertebratesen
dc.subjectTranscription Factorsen
dc.subjectCodonen
dc.subjectSequence Alignmenten
dc.subjectFrameshifting, Ribosomalen
dc.subjectAmino Acid Sequenceen
dc.subjectBase Sequenceen
dc.subjectConserved Sequenceen
dc.subjectOpen Reading Framesen
dc.titleASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2017en
prism.publicationNameBiology directen
prism.startingPage24
prism.volume12en
dc.identifier.doi10.17863/CAM.23669
dcterms.dateAccepted2017-10-04en
rioxxterms.versionofrecord10.1186/s13062-017-0195-0en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-10-16en
dc.contributor.orcidDinan, Adam [0000-0003-2812-1616]
dc.contributor.orcidAtkins, John F [0000-0001-7933-0165]
dc.contributor.orcidFirth, Andrew [0000-0002-7986-9520]
dc.identifier.eissn1745-6150
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (088789/Z/09/Z)
pubs.funder-project-idWELLCOME TRUST (106207/Z/14/Z)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) ERC (646891)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International