Compensation of gene dosage on the mammalian X

Development, Journal Year: 2024, Volume and Issue: 151(15)

Published: Aug. 1, 2024

Changes in gene dosage can have tremendous evolutionary potential (e.g. whole-genome duplications), but without compensatory mechanisms, they also lead to dysregulation and pathologies. Sex chromosomes are a paradigmatic example of naturally occurring differences their compensation. In species with chromosome-based sex determination, individuals within the same population necessarily show 'natural' for chromosomes. this Review, we focus on mammalian X chromosome discuss recent new insights into dosage-compensation mechanisms that evolved along emergence chromosomes, namely X-inactivation X-upregulation. We evolution genetic loci molecular players involved, as well regulatory diversity potentially different requirements compensation across species.

Language: Английский

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Specific catalytically impaired DDX3X mutants form sexually dimorphic hollow condensates

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 5, 2024

Mutations in the RNA helicase DDX3X, implicated various cancers and neurodevelopmental disorders, often impair unwinding translation. However, mechanisms underlying impairment differential interactions of DDX3X mutants with wild-type (WT) X-linked Y-linked homolog DDX3Y remain elusive. This study reveals that specific more frequently found disease form distinct hollow condensates cells. Using a combined structural, biochemical, single-molecule microscopy study, we show reduced ATPase release activities contribute to condensate formation these catalytic deficits result from inhibiting cycle at multiple steps. Proteomic investigations further demonstrate sequester WT DDX3X/DDX3Y other proteins crucial for diverse signaling pathways. enhances dynamics heterogeneous mutant/WT effectively than DDX3Y. These findings offer valuable insights into defects their DDX3Y, potentially explaining sex biases disease. Here authors find impairments cells have slower when co-condensed revealing potential DDX3X-related diseases.

Language: Английский

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G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability

Molecular Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Ribonucleoprotein (RNP) granules have been linked to translation regulation and disease, but their assembly regulatory mechanisms are not well understood. Here, we show that the RNA-binding protein G3BP1 preferentially interacts with unfolded RNA, driving of RNP granule-like condensates establish RNA-RNA interactions. These interactions limit mobility translatability sequestered mRNAs stabilize condensates. The DEAD-box RNA helicase DDX3X attenuates inside condensates, rendering dynamic enabling mRNA translation. Importantly, disease-associated catalytically inactive variants fail resolve such Inhibiting in cultured cells accelerates granule delays disassembly, indicating contribute stability cells. Our findings reveal how generate inhibitory modulated by helicases ensure availability translatability.

Language: Английский

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Phase separation in innate immune response and inflammation-related diseases

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 13, 2023

Inflammation induced by nonspecific pathogenic or endogenous danger signals is an essential mechanism of innate immune response. The responses are rapidly triggered conserved germline-encoded receptors that recognize broad patterns indicative danger, with subsequent signal amplification modular effectors, which have been the subject intense investigation for many years. Until recently, however, critical role intrinsic disorder-driven phase separation in facilitating went largely unappreciated. In this review, we discuss emerging evidences receptors, and/or interactors function as “all-or-nothing” switch-like hubs to stimulate acute and chronic inflammation. By concentrating relegating signaling components phase-separated compartments, cells construct flexible spatiotemporal distributions key events ensure rapid effective a myriad potentially harmful stimuli.

Language: Английский

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Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

ABSTRACT DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and expressed at higher levels in female brains. Mutations are associated with intellectual disability (ID) autism spectrum disorder (ASD) predominantly identified females. Using cellular mouse models, we show Ddx3x mediates sexual dimorphisms brain development a molecular, cellular, behavioral level. During cortical neuronal development, sustains female-biased signature of enhanced ribosomal biogenesis mRNA translation. Female neurons display proteins larger nucleoli, these sex obliterated by loss. regulates dendritic outgrowth sex- dose-dependent manner both male neurons, spine only neurons. Further, ablating conditionally forebrain sufficient to yield sex-specific changes developmental outcomes motor function. Together, findings pose as mediator differentiation during neurodevelopment open new avenues understand differences health disease.

Language: Английский

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