Biology:DUX4
 Generic protein structure example |
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.[1] Its misexpression is the cause of facioscapulohumeral muscular dystrophy (FSHD).
Gene
| CEN | centromeric end | TEL | telomeric end |
| NDE box | non-deleted element | PAS | polyadenylation site |
| triangle | D4Z4 repeat | trapezoid | partial D4Z4 repeat |
| white box | pLAM | gray boxes | DUX4 exons 1, 2, 3 |
| arrows | |||
| corner | promoters | straight | RNA transcripts |
| black | sense | red | antisense |
| blue | DBE-T | dashes | dicing sites |
This gene is located within a D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q35. The D4Z4 repeat array contains 11-150 D4Z4 repeats in the general population; a highly homologous D4Z4 repeat array has been identified on chromosome 10. The gene consists of three exons. Exons 1 and 2 are present in each D4Z4 repeat. Only one copy of exon 3 is present, telomeric to the D4Z4 repeat array.[2] The open reading frame (ORF) is entirely contained within exon 1 and contains two homeoboxes.[2] Exons 2 and 3 encode for the three prime untranslated region (3′-UTR).[2] In certain haplotypes, exon 3 contains a polyadenylation signal.[2] There was no evidence for transcription from standard cDNA libraries however RT-PCR and in-vitro expression experiments indicate that the ORF is transcribed.[3]
The repeat-array and ORF are conserved in other mammals.
Structure
DUX4 protein is 424 amino acids long.[2] Two homeodomains are situated at the N-terminus. A transcription-activating domain (TAD) and p300-binding domain are situated at the C-terminus. The TAD encompasses a potential nine amino acid TAD (9aaTAD).[2]
The two homeodomains and TAD have well-defined tertiary structure.[2] The region between the second homeodomain and TAD is predicted to be disordered.[2]
DUX4 transcripts can be spliced to produce either DUX4-S (short) or DUX4-FL (full length) mRNAs. DUX4-FL mRNA encodes for the entire DUX4 protein. DUX4-S mRNA encodes for a partial DUX4 protein, which lacks the transcription-activating domain.[2]
Function
DUX4 protein a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 (PITX1).[3] It likely stimulates zygotic genome activation.[citation needed]
The two homeodomains allow DUX4 protein to bind to DNA.[2] The C-terminal domain is involved in target gene activation.[2]
DUX is normally expressed in the testes, thymus, and cleavage-stage embryos.[4]
Clinical significance
Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy (FSHD).[5][6]
Overexpression of DUX4 due to translocations can cause B-cell leukemia.[4] A translocation that merges DUX4 with CIC can cause an aggressive type of sarcoma.[7]
See also
References
- ↑ "Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element". Gene 236 (1): 25–32. August 1999. doi:10.1016/S0378-1119(99)00267-X. PMID 10433963.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Schätzl, T; Kaiser, L; Deigner, HP (12 March 2021). "Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.". Orphanet Journal of Rare Diseases 16 (1): 129. doi:10.1186/s13023-021-01760-1. PMID 33712050.
- ↑ 3.0 3.1 "Entrez Gene: DUX4 Double homeobox, 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=22947.
- ↑ 4.0 4.1 "Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA". Cell Reports 25 (11): 2955–2962.e3. December 2018. doi:10.1016/j.celrep.2018.11.060. PMID 30540931.
- ↑ "A unifying genetic model for facioscapulohumeral muscular dystrophy". Science 329 (5999): 1650–3. September 2010. doi:10.1126/science.1189044. PMID 20724583. Bibcode: 2010Sci...329.1650L.
- ↑ "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis". Human Molecular Genetics 21 (20): 4419–30. October 2012. doi:10.1093/hmg/dds284. PMID 22798623.
- ↑ "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology 250 (5): 532–540. April 2020. doi:10.1002/path.5400. PMID 32073140.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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