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FLASH GENE

Symbol

DDX3X

contributors: mct/ - updated : 11-09-2019

HGNC name	DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked
HGNC id	2745

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	MRX102 Mental retardation, X-linked 102
Location	Xp11.4      Physical location : 41.192.650 - 41.209.522
Synonym name	CAP-Rf
	DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3
	DEAD/H box-3
	helicase like protein 2
	ATP-dependent RNA helicase DDX3X
	DEAD box, X isoform
	DEAD box protein 3, X-chromosomal
Synonym symbol(s)	DBX, HLP2, DDX14, DDX3, HLP2, CAP-Rf, CAP-Rf, MRX102
EC.number	3.6.4.13

DNA

TYPE	functioning gene
STRUCTURE	16.88 kb     17 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif	repetitive sequence   ALU
text structure	DNA box on chromosome X, homolog gene in NRY (non recombining region on chromosome Y), Alu element in intron 13

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001356 17 - 5433 NP_001347 73.2 662 - 2008 18628297 NM_001193417 16 - 5351 NP_001180346 - 646 - 2008 18628297 NM_001193416 17 - 5396 NP_001180345 - 661 - 2008 18628297 NM_001363819 17 - 5986 NP_001350748 - 475 - 2008 18628297

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive liver         Nervous brain diencephalon hypothalamus     Reproductive female system uterus     highly   male system testis     highly Respiratory respiratory tract trachea     predominantly Skin/Tegument skin

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal conserved Nuclear Export Signal (NES) is required for export of DDX3X from the nucleus
	one helicase ATP-binding domain
	one helicase C-terminal domain

conjugated

PhosphoP

HOMOLOGY

interspecies	homolog to murine Ddx3 (98.6pc)
	homolog to rattus Ddx3 (98.6pc)
	homolog to Drosophila Belle

intraspecies

homolog to DBY

Homologene

FAMILY	DEAD/H box protein family
	DDX3 subfamily

CATEGORY

enzyme , RNA associated

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria,outer
	intracellular,cytoplasm,cytosolic,granule
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
text	nuclear localization when not interacting with the hepatitis C virus core protein
	located predominantly in nuclear speckles and, at low levels, throughout the cytoplasm
	shuttles between the nucleus and the cytoplasm in a XPO1- dependent manner
	DDX3X nuclear localization increased in early mitotic cells (during prophase) concomitant with an increase in DDX3X expression levels

basic FUNCTION	putative RNA helicase, transcriptional regulator and functioning as a tumor suppressor
	positively involved in the initiation of protein synthesis
	essential for cell viability
	suppressor of PRPF8 mutation
	new member of the eIF4E inhibitory proteins involved in translation initiation regulation
	having regulatory roles in translation, cell growth and likely viral replication
	acting synergistically with TBK1 to stimulate the IFN promoter
	DDX3X and DICER1 are also required in promoting chromosome segregation and chromosomal localization of NCAPH (human homolog of Barr)
	acts as an EIF4E (eukaryotic initiation factor 4E)-inhibitory protein to suppress translation
	co-ordinative roles for DDX3X, EIF4E and PABPC1 in integrating environmental stress with translational regulation
	DDX3X, DDX1 and DHX9 are among the helicases that are required for the replication of a diverse range of viruses
	conserved DEAD-box RNA helicase important in a variety of fundamental cellular processes that include transcription, splicing, RNA transport, and translation
	has an oncogenic role in colorectal cancer
	plays a role in antiviral innate immunity
	plays an oncogenic role in breast cancer cells by modulating the cell cycle
	novel function of DDX3X in regulating expression and downstream functions of KLF4, a master negative regulator of the cell cycle
	multi-functional protein involved in the regulation of gene expression and additional non-conventional roles as signalling adaptor molecule that are independent of its enzymatic RNA remodeling activity
	may contribute to sex-related differences in resistance to microbes and resilience to inflammatory disease

CELLULAR PROCESS	nucleotide, RNA splicing
	protein, translation/synthesis

PHYSIOLOGICAL PROCESS

immunity/defense

text	innate immunity

PATHWAY

metabolism

signaling

a component

part of antiapoptotic protein complex associated with death receptors that contains GSK3B and cellular inhibitor of apoptosis protein-1 (BIRC2)

INTERACTION

DNA

binding

RNA

binding

small molecule	nucleotide,
	ATP binding

protein	interacts specifically with hepatitis C virus core protein, resulting in a change in intracellular location
	interacting with TDRD3
	interacting with the multi-component translation initiation factor eIF3 (major interaction partner)
	interacting with TBK1
	interacting with EIF4E, thus repressing its translation
	interacting with HIV Rev protein and XPO1
	interacting with vaccinia virus K7 protein, thus evading the innate immunity response by preventing DDX3X from inducing IFN-beta production
	DDX3X is critical for translation of CCNE1 mRNA, which provides an alternative mechanism for regulating CCNE1 expression during the cell cycle
	required to promote the localization and chromosome segregation of NCAPH
	PABP1 [poly(A)-binding protein 1] is another direct interaction partner of DDX3X
	implicated as a scaffolding adaptor that directly facilitates phosphorylation of IRF3 by IKBKE and might thus be involved in pathway-specific activation of IRF3
	DDX1 and DDX3X DEAD-box RNA helicases are known to be required for efficient HIV-1 Rev-dependent RNA export
	DDX3X modulates cell adhesion and motility and cancer cell metastasis via RAC1-mediated signaling pathway
	DDX3X may participate in antiviral innate immunity, at least in part, by translational control of PRKRA
	DDX3 regulates epigenetic transcriptional and translational activation of TP53 and colocalizes with TP53 at centrosome during mitosis to ensure proper mitotic progression and genome stability, which supports the tumor-suppressive role of DDX3X
	DDX3X binds the eIF4F complex, which we found to be required for ER stress-induced ATF4 expression
	DDX3X inhibits expression of Kruppel-like factor 4 (KLF4), a transcription factor and cell cycle repressor
	DDX3X also directly interacts with CHUK and enhances its autophosphorylation and -activation
	MAPKs and GSK3 phosphorylate GLE1 and thereby coordinate stress granules (SGs) dynamics by altering DDX3X function
	DDX3X steers MITF protein levels dictating melanoma metastatic potential and response to targeted therapy
	DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation

cell & other

REGULATION

activated by	various ribo- and deoxynucleic acids
	BPDE (Benzo[a]pyrene diol epoxide, which can promote growth, proliferation and neoplastic transformation of breast epithelial cells

Other	hepatitis C virus core
	phosphorylated by TBK1, phosphorylation required for DDX3X to stimulate IFN-beta production through a transcriptional activation mechanism

ASSOCIATED DISORDERS

corresponding disease(s)

MRX102

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in medulloblastoma, a highly aggressive cerebellar tumor affecting both children and adults

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target	potential prognostic biomarker in cancer
	System Type Disorder Pubmed cancer digestive colon Inhibition of DDX3 with the small molecule inhibitor RK-33 causes inhibition of Wnt signaling and may therefore be a promising future treatment strategy for a subset of colorectal cancers

ANIMAL & CELL MODELS

	mice lacking Ddx3x during hematopoiesis showed an altered leukocyte composition in bone marrow and spleen and a striking inability to combat infection with Listeria monocytogenes
	loss of Ddx3x results in an early post-implantation lethality in male mice