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ASXL gain-of-function truncation mutants: defective and dysregulated forms of a natural ribosomal frameshifting product?
Dinan, Adam M.; Atkins, John F.; Firth, Andrew E.
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.
Keyword(s): Ribosomal frameshifting; Translation; Protein synthesis; ASXL1; ASXL2; HCF-1; BAP1; Additional sex combs-like; Overlapping gene
Publication Date:
2017
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: University College Cork
Funder(s): Science Foundation Ireland
Citation(s): 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
Publisher(s): BioMed Central
File Format(s): application/pdf
Related Link(s): https://biologydirect.biomedcentral.com/articles/10.1186/s13062-017-0195-0
First Indexed: 2017-12-09 06:30:12 Last Updated: 2018-01-17 06:30:20