Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development

Neuron, Год журнала: 2020, Номер 106(3), С. 404 - 420.e8

Опубликована: Март 4, 2020

Язык: Английский

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Protein synthesis control in cancer: selectivity and therapeutic targeting

The EMBO Journal, Год журнала: 2022, Номер 41(8)

Опубликована: Март 22, 2022

Язык: Английский

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The molecular basis of translation initiation and its regulation in eukaryotes

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(3), С. 168 - 186

Опубликована: Дек. 5, 2023

Язык: Английский

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Cellular functions of eukaryotic RNA helicases and their links to human diseases

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 24(10), С. 749 - 769

Опубликована: Июль 20, 2023

Язык: Английский

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Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle

Molecular Cell, Год журнала: 2024, Номер 84(14), С. 2765 - 2784.e16

Опубликована: Июль 1, 2024

Язык: Английский

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A subpopulation of cortical neurons altered by mutations in the autism risk gene DDX3X

Biology Open, Год журнала: 2025, Номер 14(1)

Опубликована: Янв. 15, 2025

ABSTRACT Cell fate decisions during cortical development sculpt the identity of long-range connections that subserve complex behaviors. These are largely dictated by mutually exclusive transcription factors, including CTIP2/Bcl11b for subcerebral projection neurons and BRN1/Pou3f3 intra-telencephalic neurons. We have recently reported balance CTIP2-expressing is altered in a mouse model DDX3X syndrome, female-biased neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, significant motor challenges. Here, we studied developmental dynamics subpopulation co-expressing CTIP2 BRN1. found CTIP2+BRN1+ born early phases neurogenesis like other CTIP2+ neurons, peak expression perinatal life, persist adult brains. also excessive number prenatal mature areas Ddx3x mutant mice, translating into laminar distribution extending axons to brainstem. findings underscore critical role molecular specification health disease.

Язык: Английский

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Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

Molecular Cell, Год журнала: 2021, Номер 81(19), С. 4059 - 4075.e11

Опубликована: Авг. 25, 2021

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of biogenesis. frequently mutated Burkitt lymphoma, but the functional basis for this unknown. Here, we show that loss-of-function mutations are also enriched MYC-translocated diffuse large B cell lymphoma and reveal cooperation between mutant MYC. promotes translation mRNA encoding components core translational machinery, thereby driving global protein synthesis. Loss-of-function moderate MYC-driven synthesis, buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established cells restore full synthetic capacity by aberrant expression DDX3Y, Y chromosome homolog, which normally restricted to testis. These findings loss function can buffer highlight male lymphomas then compensate ectopic DDX3Y expression.

Язык: Английский

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DDX3X and DDX3Y are redundant in protein synthesis

RNA, Год журнала: 2021, Номер 27(12), С. 1577 - 1588

Опубликована: Сен. 17, 2021

DDX3 is a DEAD-box RNA helicase that regulates translation and encoded by the X- Y-linked paralogs DDX3X DDX3Y . While ubiquitously expressed in human tissues essential for viability, male-specific shows lower more variable expression than somatic tissues. Heterozygous genetic lesions mediate class of developmental disorders called syndrome, while loss implicated male infertility. One possible explanation female-bias syndrome encodes polypeptide with different biochemical activity. In this study, we use ribosome profiling vitro to demonstrate play functionally redundant roles translation. We find transcripts are sensitive depletion or mutation rescued complementation DDX3Y. Our data indicate proteins can complement each other context mRNA cells. not large fraction central nervous system. These findings suggest differences, differences paralog-dependent protein synthesis, underlie sex-bias DDX3X-associated diseases.

Язык: Английский

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Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

eLife, Год журнала: 2022, Номер 11

Опубликована: Июнь 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.

Язык: Английский

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The Role of DEAD-Box ATPases in Gene Expression and the Regulation of RNA–Protein Condensates

Annual Review of Biochemistry, Год журнала: 2022, Номер 91(1), С. 197 - 219

Опубликована: Март 19, 2022

DEAD-box ATPases constitute a very large protein family present in all cells, often great abundance. From bacteria to humans, they play critical roles many aspects of RNA metabolism, and due their widespread importance biology, have been characterized detail at both the structural biochemical levels. proteins function as RNA-dependent that can unwind short duplexes RNA, remodel ribonucleoprotein (RNP) complexes, or act clamps promote RNP assembly. Yet, it remains enigmatic how individual mechanistically contribute specific RNA-processing steps. Here, we review role regulation gene expression propose one common these enzymes is liquid-liquid phase separation condensates.

Язык: Английский

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