Biology:DUX4

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
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

D4Z4 array diagram
D4Z4 array with three D4Z4 repeats and the 4qA allele.
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

  1. "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. 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. 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. 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. 
  5. "A unifying genetic model for facioscapulohumeral muscular dystrophy". Science 329 (5999): 1650–3. September 2010. doi:10.1126/science.1189044. PMID 20724583. Bibcode2010Sci...329.1650L. 
  6. "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. 
  7. "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.