The variant landscape and function of DDX3X in cancer and neurodevelopmental disorders

Abstract

DDX3X and DDX3Y have similar structures and functions but their expression differs. Differences between the paralogs can lead to sex differences in development and disease.DDX3X and DDX3Y are dose sensitive in development and disease. Low levels of DDX3X lead to developmental perturbations and disease. Overexpression of DDX3X can also lead to disease.DDX3X and DDX3Y have different roles in different cancers, which can change as cancer progresses. These differences can contribute to sex differences in cancer incidence and severity.Germline DDX3X mutations can lead to intellectual disability (ID) through perturbed neurogenesis. The mutations’ impacts can vary by sex and severity.Males and females display different patterns in DDX3X-related cancer and ID. In many cancers, males have more premature termination codon (PTC)-inducing somatic DDX3X mutations, while in ID, only females have germline PTC-inducing mutations. RNA-binding proteins (RBPs) are crucial for processing, transport, translation, or suppression of RNAs [1.Gerstberger S. et al.A census of human RNA-binding proteins.Nat. Rev. Genet. 2014; 15: 829-845Crossref PubMed Scopus (1151) Google Scholar]. DEAD-box helicases (see Glossary), DDX3X and DDX3Y, are X and Y-linked paralogs that influence several steps in the RNA life cycle [2.Linder P. Dead-box proteins: a family affair—active and passive players in RNP-remodeling.Nucleic Acids Res. 2006; 34: 4168-4180Crossref PubMed Scopus (356) Google Scholar, 3.Linder P. Jankowsky E. From unwinding to clamping — the DEAD box RNA helicase family.Nat. Rev. Mol. Cell Biol. 2011; 12: 505-516Crossref PubMed Scopus (724) Google Scholar, 4.Sharma D. Jankowsky E. The Ded1/DDX3 subfamily of DEAD-box RNA helicases.Crit. Rev. Biochem. Mol. Biol. 2014; 49: 343-360Crossref PubMed Scopus (108) Google Scholar]. Their central role in RNA regulation is crucial to human development and pathophysiology. DDX3X has also been found to associate with the proteins TAP (encoded by NXF1) and CRM1 (encoded by XPO1), which promote the nuclear export of RNAs [5.Brennan C.M. et al.Protein ligands to Hur modulate its interaction with target mRNAs in vivo.J. Cell Biol. 2000; 151: 1-14Crossref PubMed Scopus (314) Google Scholar, 6.Lai M.-C. et al.The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control.Mol. Biol. Cell. 2008; 19: 12Crossref Google Scholar, 7.Yedavalli V.S.R.K. et al.Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function.Cell. 2004; 119: 381-392Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar]. In the cytoplasm, DDX3X regulates translation of a subset of ~2% of mRNAs [8.Calviello L. et al.DDX3 depletion represses translation of mRNAs with complex 5′ UTRs.Nucleic Acids Res. 2021; 49: 5336-5350Crossref PubMed Scopus (0) Google Scholar,9.Venkataramanan S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. DDX3X interacts with helix 16 of the 18S rRNA, a component of the small ribosomal subunit, and the 5′ UTR of its mRNA targets [8.Calviello L. et al.DDX3 depletion represses translation of mRNAs with complex 5′ UTRs.Nucleic Acids Res. 2021; 49: 5336-5350Crossref PubMed Scopus (0) Google Scholar,10.Oh S. et al.Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.Oncotarget. 2016; 7: 28169-28182Crossref PubMed Scopus (47) Google Scholar]. DDX3X binding has also been detected within coding sequences and 3′ UTRs, potentially for other regulatory roles [8.Calviello L. et al.DDX3 depletion represses translation of mRNAs with complex 5′ UTRs.Nucleic Acids Res. 2021; 49: 5336-5350Crossref PubMed Scopus (0) Google Scholar,10.Oh S. et al.Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.Oncotarget. 2016; 7: 28169-28182Crossref PubMed Scopus (47) Google Scholar,11.Valentin-Vega Y.A. et al.Cancer-associated DDX3X mutations drive stress granule assembly and impair global translation.Sci. Rep. 2016; 6: 25996Crossref PubMed Scopus (88) Google Scholar]. In the context of stress or overexpression, DDX3X aggregates with mRNAs in membraneless organelles (MLOs) called stress granules [12.Lai M.-C. et al.Human DDX3 interacts with the HIV-1 Tat protein to facilitate viral mRNA translation.PLoS ONE. 2013; 8e68665Google Scholar,13.Shih J.-W. et al.Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response.Biochem. J. 2012; 441: 119-129Crossref PubMed Scopus (132) Google Scholar]. When stressors trigger granule formation, they promote the movement of DDX3X binding from the 5′ UTR to the coding region, decreasing translation [10.Oh S. et al.Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.Oncotarget. 2016; 7: 28169-28182Crossref PubMed Scopus (47) Google Scholar]. If DDX3X is mutated, its functions can be disrupted and result in cancer or intellectual and developmental disabilities (IDDs) [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google Scholar, 15.Gong C. et al.Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.Mol. Cell. 2021; 81: 4059-4075.e11Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16.Patmore et al.DDX3X the of to Cell. Full Text Full Text PDF PubMed Google Scholar, et al.The DDX3X RNA helicase translation and in Rep. 27: Full Text Full Text PDF PubMed Scopus Google Scholar, et al.DDX3 translation of mRNAs to promote in Res. PubMed Scopus Google Scholar, et DDX3X mutations impair RNA and Full Text Full Text PDF PubMed Scopus Google Scholar]. in the has somatic DDX3X mutations in many and germline mutations in [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google et with and PubMed Scopus Google Scholar, et sequencing in and a PubMed Scopus Google Scholar, et and DDX3X as a in PubMed Google Scholar, of the of and 2013; PubMed Scopus Google Scholar, L. et in DDX3X are a of intellectual disability with J. Genet. 2015; Full Text Full Text PDF PubMed Google Scholar, et sequencing of response to Cell. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar]. the is the of the DDX3X protein from in In males and females different patterns of mutations. These patterns a between DDX3X and DDX3Y, as have of DDX3X and have DDX3X and DDX3Y et of expression human Res. PubMed Scopus Google Scholar, et from in and and is Genet. PubMed Scopus (0) Google Scholar, et that from to J. Genet. PubMed Scopus Google Scholar, et of X by expression in human S. PubMed Scopus Google Scholar]. DDX3X and DDX3Y as their roles in expression in development and and the DDX3X with in is for DDX3X the role of DDX3X in and facilitate variant DDX3X by sex and with DDX3X mutations have and DDX3 which can be in the in in the or in DDX3X and DDX3Y of the with contribute to to contribute to to to contribute to cancer to of contribute to contribute to contribute to with DDX3X mutations have and DDX3 which can be in the in in the or in in a In cancer and of DDX3X is mutated, a of DDX3X or DDX3Y to Differences in the or of DDX3X and DDX3Y can result in sex differences in development or disease. the differences between DDX3 paralogs facilitate of the of DDX3X mutations. DDX3X and DDX3Y proteins are similar and redundant in many Their in with differences in the S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. paralogs have CRM1 binding V.S.R.K. et al.Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function.Cell. 2004; 119: 381-392Abstract Full Text Full Text PDF PubMed Scopus (423) Google et by structures of and nuclear export to Mol. Biol. PubMed Scopus Google Scholar]. DEAD-box proteins as DDX3Y, and their have in their and et of a protein membraneless Cell. 2015; Full Text Full Text PDF PubMed Scopus Google et RNA helicases DDX3X and DDX3Y RNA through Cell. Full Text Full Text PDF PubMed Google Scholar]. DDX3X and DDX3Y proteins are with S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. DDX3X and DDX3Y can other in the translation of mRNA targets S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. can the ribosomal of S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. the DDX3Y more and translational to the of that DDX3X and DDX3Y et RNA helicases DDX3X and DDX3Y RNA through Cell. Full Text Full Text PDF PubMed Google Scholar]. DDX3X and DDX3Y expression with DDX3X and DDX3Y levels in DDX3Y is levels in the central and levels in S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google et of expression human Res. PubMed Scopus Google Scholar]. while the proteins have many and their expression patterns they have different functions in the human S. et al.DDX3X and DDX3Y are redundant in protein synthesis.RNA. 2021; 27: 1577-1588Crossref PubMed Google Scholar]. 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DDX3X and DDX3Y mutations are found in many cancers, they are mutations in in with The the roles of DDX3X and DDX3Y in cancer and its with a role for mutations in DDX3X or DDX3Y is (see are also of which is in and J. et functions and 2021; PubMed Scopus (0) Google Scholar, et al.DDX3X with in human 2015; PubMed Scopus (0) Google Scholar, S. et al.The and of and DDX3 expression in 2015; Scopus Google Scholar, et of in human Res. 2004; PubMed Scopus Google Scholar]. or in DDX3X and their with DDX3X is in and role in is in natural [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google J. et of with as a potentially for natural PubMed Scopus Google Scholar, et in 2016; PubMed Scopus (0) Google Scholar, et and of a to PubMed Scopus Google Scholar, et and of in Full Text Full Text PDF PubMed Scopus Google Scholar, et and of 7: PubMed Scopus (0) Google Scholar]. DDX3X is of the in and is with [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google Scholar]. with DDX3X of the and and in functions RNA unwinding and cycle [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google Scholar]. DDX3X mutations are more in [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google Scholar]. In the and the are from [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google Scholar]. in and of DDX3X can in other of and J. et of to response in a with Mol. Google S. et of in PubMed Scopus Google Scholar]. The role of DDX3X mutations in is but have to their role in is a of that a in males to females C. et al.Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.Mol. Cell. 2021; 81: 4059-4075.e11Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. DDX3X is in in C. et al.Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis.Mol. Cell. 2021; 81: 4059-4075.e11Abstract Full Text Full Text PDF PubMed Scopus (0) Google et with and PubMed Scopus Google et of in to PubMed Scopus Google Scholar, et of somatic coding and mutations in and PubMed Scopus Google Scholar, et and other in the of lymphoma.Nat. PubMed Scopus Google Scholar, et and of Res. 15: PubMed Scopus Google Scholar, et al.The of PubMed Scopus Google Scholar, P. et and have mutations but in the PubMed Scopus Google Scholar]. 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The DDX3X mutations the of other which can is DDX3X and [14.Jiang L. et al.Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.Nat. Genet. 2015; 47: 1061-1066Crossref PubMed Scopus (259) Google et of and and J. 2015; Full Text Full Text PDF PubMed Google Scholar]. DDX3X is in to of of and [10.Oh S. et al.Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress.Oncotarget. 2016; 7: 28169-28182Crossref PubMed Scopus (47) Google et al.DDX3X the of to Cell. Full Text Full Text PDF PubMed Google et sequencing of response to Cell. 2014; Full Text Full Text PDF PubMed Scopus Google E. of and 34: PubMed Scopus Google Scholar, et the 2012; PubMed Scopus Google Scholar, et sequencing somatic 2012; PubMed Scopus Google Scholar, et mutations target of 2012; PubMed Scopus Google Scholar, et and of PubMed Scopus Google Scholar]. 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