The human DEAD-box helicase DDX3X as a regulator of mRNA translation DOI Creative Commons

Cathal S. Ryan,

Martina Schröder

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Oct. 25, 2022

The human DEAD-box protein DDX3X is an RNA remodelling enzyme that has been implicated in various aspects of metabolism. In addition, like many proteins, it non-conventional functions are independent its enzymatic activity, e.g., acts as adaptor molecule innate immune signalling pathways. linked to several diseases. For example, somatic mutations were identified cancers, and de novo germline cause a neurodevelopmental condition now termed ‘DDX3X syndrome’. also important host factor different viral infections, where can have pro-or anti-viral effects depending on the specific virus. regulation translation initiation for mRNA transcripts likely central cellular function DDX3X, yet questions regarding exact targets mechanisms action remain unanswered. this review, we explore current knowledge about DDX3X’s physiological summarise interactions with machinery. A role translational reprogramming during stress emerging, may be involved granule formation mediating non-canonical initiation. Finally, discuss DDX3X-mediated infections. Dysregulation contributes involvement disease pathophysiology. Thus, better understanding regulating important, so potentially develop therapeutic strategies overcoming negative dysregulation.

Language: Английский

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model DOI Creative Commons
Mariah L. Hoye, Lorenzo Calviello, Abigail Poff

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 28, 2022

Mutations in the RNA helicase, DDX3X , are a leading cause of Intellectual Disability and present as syndrome, neurodevelopmental disorder associated with cortical malformations autism. Yet, cellular molecular mechanisms by which controls development largely unknown. Here, using mouse model Ddx3x loss-of-function we demonstrate that directs translational cell cycle control neural progenitors, underlies precise corticogenesis. First, show brain is sensitive to dosage; complete loss from progenitors causes microcephaly females, whereas hemizygous males heterozygous females reduced neurogenesis without marked microcephaly. In addition, sexually dimorphic, its paralog, Ddx3y compensates for developing male neocortex. Using live imaging promotes neuronal generation regulating both duration neurogenic divisions. Finally, use ribosome profiling vivo discover repertoire translated transcripts including those DDX3X-dependent essential neurogenesis. Our study reveals invaluable new insights into etiology implicating dysregulated progenitor dynamics translation pathogenic mechanisms.

Language: Английский

Citations

44
Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation DOI Creative Commons
Elizabeth J. Radford,

Hong-Kee Tan,

Malin H. L. Andersson

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 6, 2023

Loss-of-function of DDX3X is a leading cause neurodevelopmental disorders (NDD) in females. also somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing DDX3X, testing vitro the functional impact 12,776 nucleotide variants. identify 3432 functionally abnormal variants, three distinct classes. train machine learning classifier variants NDD-relevance. This has at least 97% sensitivity 99% specificity detect pathogenic for NDD, substantially out-performing silico predictors, resolving up 93% uncertain significance. Moreover, functionally-abnormal can account almost all excess nonsynonymous somatic mutations seen DDX3X-driven cancers. Systematic maps variant effects generated experimentally tractable cell types potential transform clinical interpretation both germline disease-associated variation.

Language: Английский

Citations

33
Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease DOI Creative Commons
Daniel G. Calame, Tianyu Guo, Chen Wang

et al.

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(8), P. 1394 - 1413

Published: July 18, 2023

Language: Английский

Citations

27
DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia DOI Creative Commons
Ann‐Kristin Dicke, Adrian Pilatz, Margot J. Wyrwoll

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: March 31, 2023

Abstract Non-obstructive azoospermia, the absence of sperm in ejaculate due to disturbed spermatogenesis, represents most severe form male infertility. De novo microdeletions Y-chromosomal AZFa region are one few well-established genetic causes for NOA and routinely analysed diagnostic workup affected men. So far, it is unclear which three genes located chromosomal indispensible germ cell maturation. Here we present four different likely pathogenic loss-of-function variants gene DDX3Y identified by analysing exome sequencing data more than 1,600 infertile Three patients underwent testicular extraction revealed typical Sertoli cell-only phenotype. One was proven be de novo. Consequently, key spermatogenic factor screening should included workflow.

Language: Английский

Citations

25
Making Ramón y Cajal proud: Development of cell identity and diversity in the cerebral cortex DOI
Daniela J. Di Bella, Nuria Domıńguez-Iturza, Juliana Brown

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(13), P. 2091 - 2111

Published: May 15, 2024

Language: Английский

Citations

15
Stress granule and P-body clearance: Seeking coherence in acts of disappearance DOI
J. Ross Buchan

Seminars in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 159-160, P. 10 - 26

Published: Jan. 25, 2024

Language: Английский

Citations

9
DDX3 Activates CBC-eIF3–Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC DOI Open Access

Hung-Hsi Chen,

Hsin-I Yu,

Muh‐Hwa Yang

et al.

Cancer Research, Journal Year: 2018, Volume and Issue: 78(16), P. 4512 - 4523

Published: June 19, 2018

Abstract Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles regulating gene expression cellular signaling. Here, we show that high levels head neck squamous cell carcinoma (HNSCC) correlate with lymph node poor prognosis demonstrate is essential for proliferation, invasion, oral (OSCC) cells. Microarray analyses revealed required a set pro-metastatic genes, including ATF4-modulated genes an aggressive OSCC line. activated translation ATF4 downstream targets, all which contain upstream open reading frames (uORF). promoted these likely by skipping inhibitory uORF. specifically enhanced association cap-binding complex (CBC) uORF-containing mRNAs facilitated recruitment eukaryotic initiation factor 3 (eIF3). CBC certain eIF3 subunits contributed to metastatic-related expression. Taken together, our results indicate role novel DDX3–CBC–eIF3 translational promoting metastasis. Significance: The discovery DDX3-mediated oncogenic expands knowledge on control mechanisms provides potential targets therapy. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4512/F1.large.jpg Cancer Res; 78(16); 4512–23. ©2018 AACR.

Language: Английский

Citations

77
DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma DOI Creative Commons

Deanna M. Patmore,

Amir Jassim,

Erica Nathan

et al.

Developmental Cell, Journal Year: 2020, Volume and Issue: 54(4), P. 455 - 470.e5

Published: June 17, 2020

Language: Английский

Citations

65
Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation DOI Creative Commons

Chris Balak,

Marianne Bénard, Élise Schaefer

et al.

The American Journal of Human Genetics, Journal Year: 2019, Volume and Issue: 105(3), P. 509 - 525

Published: Aug. 15, 2019

Language: Английский

Citations

62
Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing DOI Open Access
Ange‐Line Bruel, Sophie Nambot,

Virginie Quéré

et al.

European Journal of Human Genetics, Journal Year: 2019, Volume and Issue: 27(10), P. 1519 - 1531

Published: June 23, 2019

Language: Английский

Citations

58