ID DUX4_HUMAN Reviewed; 424 AA.
AC Q9UBX2; E2JJS1;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2001, sequence version 2.
DT 24-JAN-2024, entry version 169.
DE RecName: Full=Double homeobox protein 4 {ECO:0000312|HGNC:HGNC:50800};
DE AltName: Full=Double homeobox protein 10 {ECO:0000312|EMBL:AAK91509.1};
GN Name=DUX4 {ECO:0000312|HGNC:HGNC:50800}; Synonyms=DUX10;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND INVOLVEMENT IN FSHD1.
RX PubMed=10433963; DOI=10.1016/s0378-1119(99)00267-x;
RA Gabrieels J., Beckers M.-C., Ding H., De Vriese A., Plaisance S.,
RA van der Maarel S.M., Padberg G.W., Frants R.R., Hewitt J.E., Collen D.,
RA Belayew A.;
RT "Nucleotide sequence of the partially deleted D4Z4 locus in a patient with
RT FSHD identifies a putative gene within each 3.3 kb element.";
RL Gene 236:25-32(1999).
RN [2] {ECO:0000312|EMBL:ADN68617.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE (ISOFORMS 1 AND 2).
RC TISSUE=Skeletal muscle {ECO:0000312|EMBL:ADN68617.1};
RX PubMed=21060811; DOI=10.1371/journal.pgen.1001181;
RA Snider L., Geng L.N., Lemmers R.J., Kyba M., Ware C.B., Nelson A.M.,
RA Tawil R., Filippova G.N., van der Maarel S.M., Tapscott S.J., Miller D.G.;
RT "Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed
RT gene.";
RL PLoS Genet. 6:E1001181-E1001181(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Leclercq I., Matteotti C., Deneubourg G., Leo O., Van der Maarel S.M.,
RA Frants R.R., Padberg G.W., Coppee F., Belayew A.;
RT "A subtelomeric exchange between chromosomes 4q35 and 10q26 observed in a
RT patient with FSHD maintains a double homeobox (DUX) gene within the 3.3 kb
RT repeats of the D4Z4 locus.";
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=15709750; DOI=10.1021/bi047992w;
RA Oestlund C., Garcia-Carrasquillo R.M., Belayew A., Worman H.J.;
RT "Intracellular trafficking and dynamics of double homeodomain proteins.";
RL Biochemistry 44:2378-2384(2005).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17984056; DOI=10.1073/pnas.0708659104;
RA Dixit M., Ansseau E., Tassin A., Winokur S., Shi R., Qian H., Sauvage S.,
RA Matteotti C., van Acker A.M., Leo O., Figlewicz D., Barro M.,
RA Laoudj-Chenivesse D., Belayew A., Coppee F., Chen Y.W.;
RT "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes
RT a transcriptional activator of PITX1.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:18157-18162(2007).
RN [7]
RP INVOLVEMENT IN FSHD1.
RX PubMed=19320656; DOI=10.1111/j.1399-0004.2009.01158.x;
RA Mostacciuolo M.L., Pastorello E., Vazza G., Miorin M., Angelini C.,
RA Tomelleri G., Galluzzi G., Trevisan C.P.;
RT "Facioscapulohumeral muscular dystrophy: epidemiological and molecular
RT study in a north-east Italian population sample.";
RL Clin. Genet. 75:550-555(2009).
RN [8]
RP FUNCTION.
RX PubMed=24145033; DOI=10.1074/jbc.m113.504522;
RA Dmitriev P., Stankevicins L., Ansseau E., Petrov A., Barat A., Dessen P.,
RA Robert T., Turki A., Lazar V., Labourer E., Belayew A., Carnac G.,
RA Laoudj-Chenivesse D., Lipinski M., Vassetzky Y.S.;
RT "Defective regulation of microRNA target genes in myoblasts from
RT facioscapulohumeral dystrophy patients.";
RL J. Biol. Chem. 288:34989-35002(2013).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27378237; DOI=10.1038/mt.2016.111;
RA Chen J.C., King O.D., Zhang Y., Clayton N.P., Spencer C., Wentworth B.M.,
RA Emerson C.P. Jr., Wagner K.R.;
RT "Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular
RT Dystrophy Therapeutics.";
RL Mol. Ther. 24:1405-1411(2016).
RN [10]
RP FUNCTION, INTERACTION WITH EP300 AND CREBBP, DOMAIN, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF 159-GLN--GLN-326; 159-GLN--GLY-371 AND 327-ALA--LEU-424.
RX PubMed=26951377; DOI=10.1093/nar/gkw141;
RA Choi S.H., Gearhart M.D., Cui Z., Bosnakovski D., Kim M., Schennum N.,
RA Kyba M.;
RT "DUX4 recruits p300/CBP through its C-terminus and induces global H3K27
RT acetylation changes.";
RL Nucleic Acids Res. 44:5161-5173(2016).
RN [11]
RP FUNCTION.
RX PubMed=28935672; DOI=10.1242/jcs.205427;
RA Bosnakovski D., Toso E.A., Hartweck L.M., Magli A., Lee H.A.,
RA Thompson E.R., Dandapat A., Perlingeiro R.C.R., Kyba M.;
RT "The DUX4 homeodomains mediate inhibition of myogenesis and are
RT functionally exchangeable with the Pax7 homeodomain.";
RL J. Cell Sci. 130:3685-3697(2017).
RN [12]
RP FUNCTION, DEVELOPMENTAL STAGE, AND SUBCELLULAR LOCATION.
RX PubMed=28459457; DOI=10.1038/ng.3844;
RA Hendrickson P.G., Dorais J.A., Grow E.J., Whiddon J.L., Lim J.W.,
RA Wike C.L., Weaver B.D., Pflueger C., Emery B.R., Wilcox A.L., Nix D.A.,
RA Peterson C.M., Tapscott S.J., Carrell D.T., Cairns B.R.;
RT "Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage
RT genes and MERVL/HERVL retrotransposons.";
RL Nat. Genet. 49:925-934(2017).
RN [13]
RP FUNCTION.
RX PubMed=28459454; DOI=10.1038/ng.3846;
RA Whiddon J.L., Langford A.T., Wong C.J., Zhong J.W., Tapscott S.J.;
RT "Conservation and innovation in the DUX4-family gene network.";
RL Nat. Genet. 49:935-940(2017).
RN [14]
RP FUNCTION (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION (ISOFORMS 1 AND 2),
RP DOMAIN, AND MUTAGENESIS OF 160-ALA--ALA-342; 374-LEU--LEU-424 AND
RP 405-ALA--LEU-424.
RX PubMed=29618456; DOI=10.1242/bio.033977;
RA Mitsuhashi H., Ishimaru S., Homma S., Yu B., Honma Y., Beermann M.L.,
RA Miller J.B.;
RT "Functional domains of the FSHD-associated DUX4 protein.";
RL Biol. Open 7:0-0(2018).
RN [15] {ECO:0007744|PDB:5Z6Z}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1-153 IN COMPLEX WITH DNA,
RP SUBUNIT, DOMAIN, AND MUTAGENESIS OF ARG-20; ARG-23; TRP-26; ASN-69; ARG-95;
RP ARG-98; ASN-144 AND ARG-148.
RX PubMed=30322619; DOI=10.1016/j.bbrc.2018.10.056;
RA Li Y., Wu B., Liu H., Gao Y., Yang C., Chen X., Zhang J., Chen Y., Gu Y.,
RA Li J., Ma J., Gan J.;
RT "Structural basis for multiple gene regulation by human DUX4.";
RL Biochem. Biophys. Res. Commun. 505:1161-1167(2018).
RN [16] {ECO:0007744|PDB:6E8C}
RP X-RAY CRYSTALLOGRAPHY (2.12 ANGSTROMS) OF 17-155 IN COMPLEX WITH DNA,
RP FUNCTION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ARG-145 AND ALA-147.
RX PubMed=30540931; DOI=10.1016/j.celrep.2018.11.060;
RA Lee J.K., Bosnakovski D., Toso E.A., Dinh T., Banerjee S., Bohl T.E.,
RA Shi K., Orellana K., Kyba M., Aihara H.;
RT "Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA.";
RL Cell Rep. 25:2955-2962(2018).
RN [17] {ECO:0007744|PDB:5Z2S, ECO:0007744|PDB:5Z2T}
RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 100-150 IN COMPLEX WITH DNA,
RP FUNCTION, AND MUTAGENESIS OF ARG-95; ARG-96; LYS-97; ARG-98; GLN-143;
RP ASN-144 AND ARG-148.
RX PubMed=29572508; DOI=10.1038/s41375-018-0093-1;
RA Dong X., Zhang W., Wu H., Huang J., Zhang M., Wang P., Zhang H., Chen Z.,
RA Chen S.J., Meng G.;
RT "Structural basis of DUX4/IGH-driven transactivation.";
RL Leukemia 32:1466-1476(2018).
RN [18] {ECO:0007744|PDB:6DFY}
RP X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 94-153 IN COMPLEX WITH DNA.
RX PubMed=30054554; DOI=10.1038/s41375-018-0217-7;
RA Aihara H., Shi K., Lee J.K., Bosnakovski D., Kyba M.;
RT "Comment on structural basis of DUX4/IGH-driven transactivation.";
RL Leukemia 32:2090-2092(2018).
RN [19] {ECO:0007744|PDB:6A8R}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 94-153 IN COMPLEX WITH DNA, AND
RP FUNCTION.
RX PubMed=30315230; DOI=10.1038/s41375-018-0273-z;
RA Dong X., Zhang H., Cheng N., Li K., Meng G.;
RT "DUX4HD2-DNAERG structure reveals new insight into DUX4-Responsive-
RT Element.";
RL Leukemia 33:550-553(2019).
CC -!- FUNCTION: [Isoform 1]: Transcription factor that is selectively and
CC transiently expressed in cleavage-stage embryos (PubMed:28459457).
CC Binds to double-stranded DNA elements with the consensus sequence 5'-
CC TAATCTAATCA-3' (PubMed:28459457, PubMed:28459454, PubMed:29572508,
CC PubMed:30540931, PubMed:30315230). Binds to chromatin containing
CC histone H3 acetylated at 'Lys-27' (H3K27ac) and promotes deacetylation
CC of H3K27ac. In parallel, binds to chromatin that lacks histone H3
CC acetylation at 'Lys-27' (H3K27ac) and recruits EP300 and CREBBP to
CC promote acetylation of histone H3 at 'Lys-27' at new sites
CC (PubMed:26951377). Involved in transcriptional regulation of numerous
CC genes, primarily as transcriptional activator, but mediates also
CC repression of a set of target genes (PubMed:17984056, PubMed:27378237,
CC PubMed:26951377, PubMed:28459457, PubMed:28459454, PubMed:29618456,
CC PubMed:30540931, PubMed:29572508). Promotes expression of ZSCAN4 and
CC KDM4E, two proteins with essential roles during early embryogenesis
CC (PubMed:27378237, PubMed:26951377, PubMed:28459457, PubMed:29618456).
CC Heterologous expression in cultured embryonic stem cells mediates also
CC transcription of HERVL retrotransposons and transcripts derived from
CC ACRO1 and HSATII satellite repeats (PubMed:28459457). May activate
CC expression of PITX1 (PubMed:17984056). May regulate microRNA (miRNA)
CC expression (PubMed:24145033). Inappropriate expression can inhibit
CC myogenesis and promote apoptosis (PubMed:26951377, PubMed:28935672,
CC PubMed:29618456). {ECO:0000269|PubMed:17984056,
CC ECO:0000269|PubMed:24145033, ECO:0000269|PubMed:26951377,
CC ECO:0000269|PubMed:27378237, ECO:0000269|PubMed:28459454,
CC ECO:0000269|PubMed:28459457, ECO:0000269|PubMed:28935672,
CC ECO:0000269|PubMed:29572508, ECO:0000269|PubMed:29618456,
CC ECO:0000269|PubMed:30315230, ECO:0000269|PubMed:30540931}.
CC -!- FUNCTION: [Isoform 2]: Probably inactive as a transcriptional
CC activator, due to the absence of the C-terminal region that is
CC important for transcriptional activation. Can inhibit transcriptional
CC activation mediated by isoform 1. Heterologous expression of isoform 2
CC has no deleterious effect on cell survival.
CC {ECO:0000269|PubMed:29618456}.
CC -!- SUBUNIT: Binds DNA as a monomer (PubMed:30322619, PubMed:30540931).
CC Interacts (via C-terminus) with EP300 and CREBBP (PubMed:26951377).
CC {ECO:0000269|PubMed:26951377, ECO:0000269|PubMed:30322619,
CC ECO:0000269|PubMed:30540931}.
CC -!- INTERACTION:
CC Q9UBX2; P17661: DES; NbExp=3; IntAct=EBI-11600078, EBI-1055572;
CC Q9UBX2; P31001: Des; Xeno; NbExp=2; IntAct=EBI-11600078, EBI-298565;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Nucleus {ECO:0000255|PROSITE-
CC ProRule:PRU00108, ECO:0000269|PubMed:15709750,
CC ECO:0000269|PubMed:17984056, ECO:0000269|PubMed:21060811,
CC ECO:0000269|PubMed:26951377, ECO:0000269|PubMed:27378237,
CC ECO:0000269|PubMed:28459457, ECO:0000269|PubMed:29618456}.
CC Note=Actively transported through the nuclear pore complex (NPC).
CC {ECO:0000305|PubMed:15709750}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:29618456, ECO:0000305|PubMed:15709750}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=DUX4-fl {ECO:0000303|PubMed:21060811};
CC IsoId=Q9UBX2-1; Sequence=Displayed;
CC Name=2; Synonyms=DUX4-s {ECO:0000303|PubMed:21060811};
CC IsoId=Q9UBX2-2; Sequence=VSP_060075, VSP_060076;
CC -!- TISSUE SPECIFICITY: Isoform 1: Does not seem to be expressed in normal
CC muscle, but is detected in muscle of individuals with FSHD, and also in
CC testis (at protein level) (PubMed:21060811, PubMed:17984056). Isoform
CC 1: Does not seem to be expressed in normal muscle, but in muscle of
CC individuals with FSHD, where it may be toxic to cells (PubMed:21060811,
CC PubMed:17984056). Isoform 2: Detected in skeletal muscle, fibroblasts
CC and testis from healthy individuals (PubMed:21060811).
CC {ECO:0000269|PubMed:17984056, ECO:0000269|PubMed:21060811}.
CC -!- DEVELOPMENTAL STAGE: Isoform 1: Detected in embryos at the 4-cell
CC stage. Not detected in embryos at the 2-cell stage, or at the 8-cell
CC stage (at protein level). Detected in embryos at the 4-cell stage. Not
CC detected in embryos at the 2-cell stage, or at the 8-cell stage
CC (PubMed:28459457). Detected in induced pluripotent (iPS) cells, but
CC expression is suppressed upon differentiation to embryoid bodies.
CC Isoform 2: Detected in embryoid bodies derived from induced pluripotent
CC (iPS) cells, but not in the induced pluripotent (iPS) cells themselves
CC (PubMed:21060811). {ECO:0000269|PubMed:21060811,
CC ECO:0000269|PubMed:28459457}.
CC -!- DOMAIN: The two homeobox domains are arranged in a head-to-head
CC orientation when bound to double-stranded DNA, each domain binding to
CC one of the two DNA strands. Together, the homeobox domains can be
CC considered to bind DNA with the consensus sequence 5'-TAATCTAATCA-3',
CC but due to the head-to-head orientation of the DNA-bound domains, the
CC first homeobox domain binds to the consensus sequence 5'-TAAT-3', and
CC the second homeobox domain binds DNA on the opposite strand, with the
CC consensus sequence 5'-TGAT-3' (PubMed:30322619, PubMed:30540931). Both
CC homeobox domains confer nuclear targeting (PubMed:15709750).
CC {ECO:0000269|PubMed:15709750, ECO:0000269|PubMed:30322619,
CC ECO:0000269|PubMed:30540931}.
CC -!- DOMAIN: The C-terminal region is required for efficient activation of
CC transcription from target promoters (PubMed:26951377, PubMed:29618456).
CC It mediates interaction with EP300 and CREBBP (PubMed:26951377).
CC {ECO:0000269|PubMed:26951377, ECO:0000269|PubMed:29618456}.
CC -!- DISEASE: Facioscapulohumeral muscular dystrophy 1 (FSHD1) [MIM:158900]:
CC A degenerative muscle disease characterized by slowly progressive
CC weakness of the muscles of the face, upper-arm, and shoulder girdle.
CC The onset of symptoms usually occurs in the first or second decade of
CC life. Affected individuals usually present with impairment of upper
CC extremity elevation. This tends to be followed by facial weakness,
CC primarily involving the orbicularis oris and orbicularis oculi muscles.
CC {ECO:0000269|PubMed:10433963, ECO:0000269|PubMed:19320656}. Note=The
CC gene represented in this entry is involved in disease pathogenesis. The
CC disease is caused by deletion of an integral number of units of a 3.3-
CC kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome
CC 4q35. In unaffected subjects, the D4Z4 array consists of 11-150
CC repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats
CC (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is
CC epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation
CC in FSHD1 results in inefficient epigenetic repression of DUX4 and a
CC variegated pattern of DUX4 protein expression in a subset of skeletal
CC muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates
CC the expression of stem cell and germline genes, and, when overexpressed
CC in somatic cells, DUX4 can ultimately lead to cell death.
CC {ECO:0000269|PubMed:19320656}.
CC -!- MISCELLANEOUS: DUX genes are present in 3.3-kilobase elements, a tandem
CC repeat family scattered in the genome found on the short arms of all
CC acrocentric chromosomes as well as on several other chromosomes.
CC {ECO:0000269|PubMed:10433963, ECO:0000269|PubMed:17984056,
CC ECO:0000269|PubMed:19320656, ECO:0000269|PubMed:21060811}.
CC -!- SIMILARITY: Belongs to the paired homeobox family. {ECO:0000305}.
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DR EMBL; AF117653; AAD54067.2; -; Genomic_DNA.
DR EMBL; HQ266762; ADN68617.1; -; mRNA.
DR EMBL; AF117653; AAD54068.2; -; Genomic_DNA.
DR EMBL; AY044051; AAK91509.1; -; Genomic_DNA.
DR EMBL; AC215524; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS77990.1; -. [Q9UBX2-1]
DR CCDS; CCDS93681.1; -. [Q9UBX2-2]
DR RefSeq; NP_001280727.1; NM_001293798.2. [Q9UBX2-1]
DR RefSeq; NP_001292997.1; NM_001306068.2. [Q9UBX2-1]
DR RefSeq; XP_011529816.1; XM_011531514.2.
DR RefSeq; XP_016885822.1; XM_017030333.1.
DR RefSeq; XP_016885823.1; XM_017030334.1.
DR RefSeq; XP_016885824.1; XM_017030335.1.
DR RefSeq; XP_016885825.1; XM_017030336.1.
DR RefSeq; XP_016885826.1; XM_017030337.1.
DR RefSeq; XP_016885827.1; XM_017030338.1.
DR RefSeq; XP_016885828.1; XM_017030339.1.
DR RefSeq; XP_016885829.1; XM_017030340.1.
DR PDB; 5Z2S; X-ray; 1.50 A; A=100-150.
DR PDB; 5Z2T; X-ray; 2.62 A; C/D=94-153.
DR PDB; 5Z6Z; X-ray; 2.30 A; A=1-153.
DR PDB; 5ZFW; X-ray; 2.10 A; A=1-149.
DR PDB; 5ZFY; X-ray; 2.30 A; A=1-149.
DR PDB; 5ZFZ; X-ray; 1.90 A; A=1-149.
DR PDB; 6A8R; X-ray; 1.60 A; A/B=94-153.
DR PDB; 6DFY; X-ray; 2.62 A; C/D=94-153.
DR PDB; 6E8C; X-ray; 2.12 A; A=17-155.
DR PDB; 6U81; X-ray; 2.34 A; A=19-150.
DR PDB; 6U82; X-ray; 3.21 A; A/D=17-150.
DR PDBsum; 5Z2S; -.
DR PDBsum; 5Z2T; -.
DR PDBsum; 5Z6Z; -.
DR PDBsum; 5ZFW; -.
DR PDBsum; 5ZFY; -.
DR PDBsum; 5ZFZ; -.
DR PDBsum; 6A8R; -.
DR PDBsum; 6DFY; -.
DR PDBsum; 6E8C; -.
DR PDBsum; 6U81; -.
DR PDBsum; 6U82; -.
DR AlphaFoldDB; Q9UBX2; -.
DR SMR; Q9UBX2; -.
DR BioGRID; 940343; 259.
DR IntAct; Q9UBX2; 285.
DR TCDB; 1.I.1.1.3; the nuclear pore complex (npc) family.
DR iPTMnet; Q9UBX2; -.
DR PhosphoSitePlus; Q9UBX2; -.
DR BioMuta; DUX4; -.
DR DMDM; 74720085; -.
DR MassIVE; Q9UBX2; -.
DR PeptideAtlas; Q9UBX2; -.
DR Antibodypedia; 73101; 314 antibodies from 22 providers.
DR DNASU; 100288687; -.
DR Ensembl; ENST00000565211.1; ENSP00000458065.1; ENSG00000260596.5. [Q9UBX2-1]
DR Ensembl; ENST00000569241.5; ENSP00000456539.1; ENSG00000260596.5. [Q9UBX2-1]
DR Ensembl; ENST00000570263.5; ENSP00000455112.1; ENSG00000260596.5. [Q9UBX2-2]
DR Ensembl; ENST00000616166.1; ENSP00000483555.1; ENSG00000260596.5. [Q9UBX2-1]
DR Ensembl; ENST00000637517.3; ENSP00000489958.1; ENSG00000283949.3. [Q9UBX2-1]
DR Ensembl; ENST00000710433.1; ENSP00000518267.1; ENSG00000283949.3. [Q9UBX2-1]
DR Ensembl; ENST00000710434.1; ENSP00000518268.1; ENSG00000283949.3. [Q9UBX2-2]
DR GeneID; 100288687; -.
DR KEGG; hsa:100288687; -.
DR MANE-Select; ENST00000565211.1; ENSP00000458065.1; NM_001306068.3; NP_001292997.1.
DR UCSC; uc031tgs.2; human. [Q9UBX2-1]
DR UCSC; uc063bru.1; human.
DR AGR; HGNC:50800; -.
DR CTD; 100288687; -.
DR DisGeNET; 100288687; -.
DR GeneCards; DUX4; -.
DR GeneReviews; DUX4; -.
DR HGNC; HGNC:50800; DUX4.
DR HPA; ENSG00000260596; Not detected.
DR MalaCards; DUX4; -.
DR MIM; 158900; phenotype.
DR MIM; 606009; gene.
DR neXtProt; NX_Q9UBX2; -.
DR OpenTargets; ENSG00000260596; -.
DR Orphanet; 269; Facioscapulohumeral dystrophy.
DR VEuPathDB; HostDB:ENSG00000260596; -.
DR eggNOG; KOG0849; Eukaryota.
DR GeneTree; ENSGT00940000154537; -.
DR HOGENOM; CLU_045070_0_0_1; -.
DR InParanoid; Q9UBX2; -.
DR OMA; QTCFERN; -.
DR OrthoDB; 4740964at2759; -.
DR PhylomeDB; Q9UBX2; -.
DR PathwayCommons; Q9UBX2; -.
DR Reactome; R-HSA-9819196; Zygotic genome activation (ZGA).
DR SignaLink; Q9UBX2; -.
DR SIGNOR; Q9UBX2; -.
DR BioGRID-ORCS; 100288687; 13 hits in 113 CRISPR screens.
DR ChiTaRS; DUX4; human.
DR GenomeRNAi; 100288687; -.
DR Pharos; Q9UBX2; Tbio.
DR PRO; PR:Q9UBX2; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9UBX2; Protein.
DR Bgee; ENSG00000260596; Expressed in primordial germ cell in gonad and 60 other cell types or tissues.
DR ExpressionAtlas; Q9UBX2; baseline and differential.
DR Genevisible; Q9UBX2; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0070317; P:negative regulation of G0 to G1 transition; IDA:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR CDD; cd00086; homeodomain; 2.
DR Gene3D; 1.10.10.60; Homeodomain-like; 2.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR000047; HTH_motif.
DR PANTHER; PTHR46123:SF3; DOUBLE HOMEOBOX PROTEIN 1-RELATED; 1.
DR PANTHER; PTHR46123; MIX-TYPE HOMEOBOX GENE 1-RELATED; 1.
DR Pfam; PF00046; Homeodomain; 2.
DR PRINTS; PR00031; HTHREPRESSR.
DR SMART; SM00389; HOX; 2.
DR SUPFAM; SSF46689; Homeodomain-like; 2.
DR PROSITE; PS50071; HOMEOBOX_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Developmental protein;
KW DNA-binding; Homeobox; Nucleus; Reference proteome; Repeat; Transcription;
KW Transcription regulation.
FT CHAIN 1..424
FT /note="Double homeobox protein 4"
FT /id="PRO_0000252413"
FT DNA_BIND 19..78
FT /note="Homeobox 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000269|PubMed:30540931"
FT DNA_BIND 94..153
FT /note="Homeobox 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000269|PubMed:30540931"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 72..102
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 218..362
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 327..424
FT /note="Required for interaction with EP300 and CREBBP, and
FT for transcriptional activation of target genes"
FT /evidence="ECO:0000269|PubMed:26951377"
FT REGION 388..414
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 405..424
FT /note="Important for transcriptional activation of target
FT genes"
FT /evidence="ECO:0000269|PubMed:29618456"
FT COMPBIAS 72..96
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 341..355
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 160
FT /note="A -> V (in isoform 2)"
FT /id="VSP_060075"
FT VAR_SEQ 161..424
FT /note="Missing (in isoform 2)"
FT /id="VSP_060076"
FT MUTAGEN 20
FT /note="R->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 23
FT /note="R->A: Mildly decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 26
FT /note="W->A: No effect on DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 69
FT /note="N->A: Mildly decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 95
FT /note="R->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 95
FT /note="R->A: No effect on DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 96
FT /note="R->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 97
FT /note="K->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 98
FT /note="R->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508,
FT ECO:0000269|PubMed:30322619"
FT MUTAGEN 143
FT /note="Q->E: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 144
FT /note="N->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 144
FT /note="N->E: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 145
FT /note="R->E: Altered sequence specificity, with increased
FT affinity for the DNA sequence 5'-TAATCTAATTA-3'."
FT /evidence="ECO:0000269|PubMed:30540931"
FT MUTAGEN 147
FT /note="A->S: Altered sequence specificity, with increased
FT affinity for the DNA sequence 5'-TAATCTAATTA-3'."
FT /evidence="ECO:0000269|PubMed:30540931"
FT MUTAGEN 148
FT /note="R->A: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:30322619"
FT MUTAGEN 148
FT /note="R->E: Decreased DNA binding affinity."
FT /evidence="ECO:0000269|PubMed:29572508"
FT MUTAGEN 159..371
FT /note="Missing: Decreased activity as transcriptional
FT activator."
FT /evidence="ECO:0000269|PubMed:26951377"
FT MUTAGEN 159..326
FT /note="Missing: No effect on activity as transcriptional
FT activator."
FT /evidence="ECO:0000269|PubMed:26951377"
FT MUTAGEN 160..342
FT /note="Missing: No effect on activity as transcriptional
FT activator."
FT /evidence="ECO:0000269|PubMed:29618456"
FT MUTAGEN 327..424
FT /note="Missing: Loss of interaction with EP300 and CREBBP."
FT /evidence="ECO:0000269|PubMed:26951377"
FT MUTAGEN 374..424
FT /note="Missing: Abolishes activity as transcriptional
FT activator."
FT /evidence="ECO:0000269|PubMed:29618456"
FT MUTAGEN 405..424
FT /note="Missing: Reduced activity as transcriptional
FT activator."
FT /evidence="ECO:0000269|PubMed:29618456"
FT HELIX 28..40
FT /evidence="ECO:0007829|PDB:5ZFZ"
FT HELIX 46..56
FT /evidence="ECO:0007829|PDB:5ZFZ"
FT HELIX 60..81
FT /evidence="ECO:0007829|PDB:5ZFZ"
FT HELIX 103..113
FT /evidence="ECO:0007829|PDB:5Z2S"
FT HELIX 121..131
FT /evidence="ECO:0007829|PDB:5Z2S"
FT HELIX 135..148
FT /evidence="ECO:0007829|PDB:5Z2S"
SQ SEQUENCE 424 AA; 44940 MW; C51E9EE25C6661B8 CRC64;
MALPTPSDST LPAEARGRGR RRRLVWTPSQ SEALRACFER NPYPGIATRE RLAQAIGIPE
PRVQIWFQNE RSRQLRQHRR ESRPWPGRRG PPEGRRKRTA VTGSQTALLL RAFEKDRFPG
IAAREELARE TGLPESRIQI WFQNRRARHP GQGGRAPAQA GGLCSAAPGG GHPAPSWVAF
AHTGAWGTGL PAPHVPCAPG ALPQGAFVSQ AARAAPALQP SQAAPAEGIS QPAPARGDFA
YAAPAPPDGA LSHPQAPRWP PHPGKSREDR DPQRDGLPGP CAVAQPGPAQ AGPQGQGVLA
PPTSQGSPWW GWGRGPQVAG AAWEPQAGAA PPPQPAPPDA SASARQGQMQ GIPAPSQALQ
EPAPWSALPC GLLLDELLAS PEFLQQAQPL LETEAPGELE ASEEAASLEA PLSEEEYRAL
LEEL
//
