DDX3X explained

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.[1] [2] [3]

Function

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which interacts specifically with hepatitis C virus core protein resulting a change in intracellular location. This gene has a homolog located in the nonrecombining region of the Y chromosome. The protein sequence is 91% identical between this gene and the Y-linked homolog.[3]

Sub-cellular trafficking

DDX3X performs its functions in the cell nucleus and cytoplasm, exiting the nucleus via the exportin-1/CRM1 nuclear export pathway. It was initially reported that the DDX3X helicase domain was necessary for this interaction, while the canonical features of the trafficking pathway, namely the presence of a nuclear export signal (NES) on DDX3X and Ran-GTP binding to exportin-1, were dispensable.[4] DDX3X binding to, and trafficking by, exportin-1 has since been shown not to require the DDX3X helicase domain and be explicitly NES- and Ran-GTP-dependent.[5]

Role in cancer

DDX3X is involved in many different types of cancer. For example, it is abnormally expressed in breast epithelial cancer cells in which its expression is activated by HIF1A during hypoxia.[6] Increased expression of DDX3X by HIF1A in hypoxia is initiated by the direct binding of HIF1A to the HIF1A response element, as verified with chromatin immunoprecipitation and luciferase reporter assay. Since the expression of DDX3X is affected by the activity of HIF1A, the co-localization of these proteins has also been demonstrated in MDA-MB-231 xenograft tumor samples.

In HeLa cells DDX3X is reported to control cell cycle progression through Cyclin E1.[7] More specifically, DDX3X was shown to directly bind to the 5´ UTR of Cyclin E1 and thereby facilitating the translation of the protein. Increased protein levels of Cyclin E1 was demonstrated to mediate the transition of S phase entry.

Melanoma survival, migration and proliferation is affected by DDX3X activity.[8] Melanoma cells with low DDX3X expression exhibit a high migratory capacity, low proliferation rate and reduced vemurafenib sensitivity. While high DDX3X expressing cells are drug sensitive, more proliferative and less migratory. These phenotypes can be explained by the translational effects on the melanoma transcription factor MITF. The 5' UTR of the MITF mRNA contains a complex RNA regulon (IRES) that is bound and activated by DDX3X. Activation of the IRES leads to translation of the MITF mRNA. Mice injected with melanoma cells with a deleted IRES display more aggressive tumor progression including increased lung metastasis. Interestingly, the DDX3X in melanoma is affected by vemurafenib via an undiscovered mechanism. It is unknown how DDX3X is downregulated by the presence of vemurafenib. However, reduced levels of DDX3X during drug treatment explains the development of drug resistant cells frequently detected with low MITF expression.[9] [10]

Clinical significance

Mutations of the DDX3X gene are associated with medulloblastoma.[11] [12] [13] In melanoma the low expression of the gene is linked to a poor distant metastasis free survival. In addition, the mRNA level of DDX3X is lower in matched post-relapse melanoma biopsies for patients receiving vemurafenib and in progressing tumors.

Mutations of the DDX3X gene also cause DDX3X syndrome, which affects predominantly females and presents with developmental delay or disability, autism, ADHD, and low muscle tone.

See also

Further reading

Notes and References

  1. Lahn BT, Page DC . Functional coherence of the human Y chromosome . Science . 278 . 5338 . 675–80 . October 1997 . 9381176 . 10.1126/science.278.5338.675 . 1997Sci...278..675L .
  2. Park SH, Lee SG, Kim Y, Song K . Assignment of a human putative RNA helicase gene, DDX3, to human X chromosome bands p11.3→p11.23 . Cytogenetics and Cell Genetics . 81 . 3–4 . 178–9 . Oct 1998 . 9730595 . 10.1159/000015022 . 46774908 .
  3. Web site: Entrez Gene: DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked.
  4. Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT . Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function . en . Cell . 119 . 3 . 381–92 . October 2004 . 15507209 . 10.1016/j.cell.2004.09.029 . free .
  5. Heaton SM, Atkinson SC, Sweeney MN, Yang SN, Jans DA, Borg NA . Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity . Cells . 8 . 10 . 1181 . September 2019 . 31575075 . 10.3390/cells8101181 . 6848931 . free .
  6. Botlagunta M, Krishnamachary B, Vesuna F, Winnard PT, Bol GM, Patel AH, Raman V . Expression of DDX3 is directly modulated by hypoxia inducible factor-1 alpha in breast epithelial cells . PLOS ONE . 6 . 3 . e17563 . March 2011 . 21448281 . 10.1371/journal.pone.0017563 . 3063174. 2011PLoSO...617563B . free .
  7. Lai MC, Chang WC, Shieh SY, Tarn WY . DDX3 regulates cell growth through translational control of cyclin E1 . Molecular and Cellular Biology . 30 . 22 . 5444–53 . November 2010 . 20837705 . 10.1128/MCB.00560-10 . 2976371.
  8. Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, Lauss M, Cabrita R, Cordero E, Bosch A, Rosengren F, Häkkinen J, Griewank K, Paschen A, Harbst K, Olsson H, Ingvar C, Carneiro A, Tsao H, Schadendorf D, Pietras K, Bellodi C, Jönsson G . The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma . Cell Reports . 27 . 12 . 3573–3586.e7 . June 2019 . 31216476 . 10.1016/j.celrep.2019.05.069 . free .
  9. Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Geukes Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS . Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma . Nature Communications . 5 . 1 . 5712 . December 2014 . 25502142 . 4428333 . 10.1038/ncomms6712 . 2014NatCo...5.5712M .
  10. Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, Frederick DT, Barzily-Rokni M, Straussman R, Haq R, Fisher DE, Mesirov JP, Hahn WC, Flaherty KT, Wargo JA, Tamayo P, Garraway LA . A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors . Cancer Discovery . 4 . 7 . 816–27 . July 2014 . 24771846 . 4154497 . 10.1158/2159-8290.CD-13-0424 .
  11. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S, Zhao D, Kawauchi D, Roussel MF, Finkelstein D, Ellison DW, Lau CC, Bouffet E, Hassall T, Gururangan S, Cohn R, Fulton RS, Fulton LL, Dooling DJ, Ochoa K, Gajjar A, Mardis ER, Wilson RK, Downing JR, Zhang J, Gilbertson RJ . Novel mutations target distinct subgroups of medulloblastoma . Nature . 488 . 7409 . 43–8 . August 2012 . 22722829 . 10.1038/nature11213 . 3412905. 2012Natur.488...43R .
  12. Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P . Dissecting the genomic complexity underlying medulloblastoma . Nature . 488 . 7409 . 100–5 . August 2012 . 22832583 . 3662966 . 10.1038/nature11284 . 2012Natur.488..100J .
  13. Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ . Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations . Nature . 488 . 7409 . 106–10 . August 2012 . 22820256 . 3413789 . 10.1038/nature11329 . 2012Natur.488..106P .

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