A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis DOI Creative Commons
Nic Robertson, Vadim Shchepachev, David J. Wright

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 3, 2022

RMRP encodes a non-coding RNA forming the core of RNase MRP ribonucleoprotein complex. Mutations cause Cartilage Hair Hypoplasia (CHH), characterized by skeletal abnormalities and impaired T cell activation. Yeast cleaves specific site in pre-ribosomal (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations impair mouse activation delay processing. Patient-derived fibroblasts CHH-linked showed similar processing delay. Human engineered most common CHH mutation (70

Language: Английский

The nucleolus as a multiphase liquid condensate DOI
Denis L. J. Lafontaine, Joshua A. Riback, Rümeyza Bascetin

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(3), P. 165 - 182

Published: Sept. 1, 2020

Language: Английский

Citations

784
A guide to membraneless organelles and their various roles in gene regulation DOI
Tetsuro Hirose,

Kensuke Ninomiya,

Shinichi Nakagawa

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(4), P. 288 - 304

Published: Nov. 23, 2022

Language: Английский

Citations

297
Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy DOI Creative Commons
Jian Kang, Natalie Brajanovski, Keefe T. Chan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 30, 2021

Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth proliferation. The ribosomal proteins (RPs), comprising the structural parts of ribosome, essential ribosome assembly function. In addition to their canonical functions, multiple RPs have extra-ribosomal functions including activation p53-dependent or p53-independent pathways in response stress, resulting cycle arrest apoptosis. Defects biogenesis, translation, individual RPs, mutations been linked a diverse range human congenital disorders termed ribosomopathies. Ribosomopathies characterized by tissue-specific phenotypic abnormalities higher cancer risk later life. Recent discoveries somatic tumor types reinforce connections between defects cancer. this article, we review most recent advances understanding molecular consequences RP ribosomopathies We particularly discuss basis transition from hypo- hyper-proliferation with elevated risk, paradox "Dameshek's riddle." Furthermore, current treatments prospective therapies targeting defects. also highlight stress-based therapeutics. Importantly, insights into mechanisms resistance bring new perspectives susceptibility clinical implications therapy.

Language: Английский

Citations

258
Ribosome biogenesis factors—from names to functions DOI Creative Commons
Kerstin Dörner, Chiara Ruggeri, Ivo Zemp

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(7)

Published: Feb. 10, 2023

Abstract The assembly of ribosomal subunits is a highly orchestrated process that involves huge cohort accessory factors. Most eukaryotic ribosome biogenesis factors were first identified by genetic screens and proteomic approaches pre‐ribosomal particles in Saccharomyces cerevisiae . Later, research on human synthesis not only demonstrated the requirement for many these conserved evolution, but also revealed involvement additional players, reflecting more complex pathway mammalian cells. Yet, it remained challenge field to assign function reveal their molecular mode action. Over past decade, structural, biochemical, cellular studies have largely filled this gap knowledge led detailed understanding role players during stepwise maturation. Such will be key further understand better treat diseases linked disturbed assembly, including ribosomopathies, as well different types cancer.

Language: Английский

Citations

100
Shared and distinct mechanisms of UBA1 inactivation across different diseases DOI Creative Commons
Jason C. Collins, Samuel J. Magaziner, Maya English

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(10), P. 1919 - 1946

Published: Feb. 15, 2024

Abstract Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little known about the underlying molecular mechanisms. Here, dissecting VEXAS-causing mutations, we discovered that p.Met41 alter cytoplasmic isoform expression, whereas other reduce catalytic activity nuclear isoforms diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 most prominently affect transthioesterification, revealing transfer enzymes as a shared property pathogenesis amongst different syndrome genotypes. A similar charging bottleneck exists in some lung cancer-associated but not spinal muscular atrophy-causing instead, render thermolabile. Collectively, our results highlight precision conformational changes required for faithful transfer, define distinct mechanisms inactivation diseases, suggest specific E1-E2 modules control aspects tissue differentiation maintenance.

Language: Английский

Citations

20
The impact of ribosome biogenesis in cancer: from proliferation to metastasis DOI Creative Commons
Sseu-Pei Hwang, Catherine Denicourt

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(2)

Published: April 8, 2024

Abstract The dysregulation of ribosome biogenesis is a hallmark cancer, facilitating the adaptation to altered translational demands essential for various aspects tumor progression. This review explores intricate interplay between and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal multifaceted roles ribosomes, extending beyond protein factories include regulatory functions in mRNA translation. Dysregulated not only hampers precise control global production proliferation but also influences processes such as maintenance stem cell-like properties epithelial-mesenchymal transition, contributing Interference with biogenesis, notably through RNA Pol I inhibition, elicits stress response marked nucleolar integrity loss, subsequent G1-cell cycle arrest or cell death. These findings suggest that cells may rely on heightened transcription, rendering ribosomal synthesis potential therapeutic vulnerability. further targeting vulnerabilities promising strategy disrupt production, presenting opportunities treatment.

Language: Английский

Citations

19
RNF10 and RIOK3 facilitate 40S ribosomal subunit degradation upon 60S biogenesis disruption or amino acid starvation DOI Creative Commons
Pierce W. Ford, Danielle M. Garshott,

Meena L. Narasimhan

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115371 - 115371

Published: Feb. 28, 2025

Highlights•Depletion of 60S subunits or amino acid starvation activates the iRQC pathway•RNF10 expression is regulated via a translation control mechanism utilizing conserved uORFs•RNF10 acts on 40S engaged with mRNA•RIOK3 ubiquitin binding and kinase activity are required for iRQC-mediated degradationSummaryThe initiation-specific ribosome-associated quality pathway (iRQC) activated when initiation complexes fail to transition elongation-competent 80S ribosomes. Upon activation, RNF10 ubiquitylates proteins uS3 uS5, which leads decay. How in absence pharmacological inhibitors what mechanisms govern capacity remain unanswered questions. Here, we demonstrate that altering 60S:40S stoichiometry by disrupting biogenesis triggers activation Depleting critical scanning helicase eIF4A1 impairs ubiquitylation degradation, indicating mRNA engagement iRQC. We show conditions also stimulate iRQC-dependent identify RIOK3 as crucial factor interacts ubiquitylated mediate degradation. Both protein levels increase upon establishing feedforward regulates subsequent decay.Graphical abstract

Language: Английский

Citations

3
Nucleolar maturation of the human small subunit processome DOI
Sameer Singh, Arnaud Vanden Broeck, Linamarie Miller

et al.

Science, Journal Year: 2021, Volume and Issue: 373(6560)

Published: Sept. 9, 2021

The human small subunit processome mediates early maturation of the ribosomal by coupling RNA folding to subsequent cleavage and processing steps. We report high-resolution cryo–electron microscopy structures maturing (SSU) processomes at resolutions 2.7 3.9 angstroms. These reveal molecular mechanisms that enable crucial progressions during SSU maturation. states within these particles are communicated coordinated with key enzymes drive irreversible steps such as targeted exosome-mediated degradation, protein-guided site-specific endonucleolytic cleavage, tightly controlled unwinding. conserved highlight processome’s impressive structural plasticity, which endows this 4.5-megadalton nucleolar assembly distinctive ability mature from within.

Language: Английский

Citations

102
The Role of RNA Binding Proteins for Local mRNA Translation: Implications in Neurological Disorders DOI Creative Commons
Maximilian Paul Thelen, Min Jeong Kye

Frontiers in Molecular Biosciences, Journal Year: 2020, Volume and Issue: 6

Published: Jan. 14, 2020

As neurons are one of the most highly polarized cells in our body, they require sophisticated cellular mechanisms to maintain protein homeostasis their subcellular compartments such as axons and dendrites. When neuronal is disturbed due genetic mutations or deletions, this often results degeneration leading devastating outcome spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) fragile X syndrome (FXS). Ribonucleoprotein (RNP) complexes macromolecular composed RNA binding proteins (RBPs) target RNAs. RBPs contain domains bind molecules via specific sequence motifs. RNP have various functions gene expression including messenger (mRNA) trafficking, processing silencing. In neurons, deliver sets mRNAs dendrites be locally translated. Mutations deletions genes coding for RNPs been reported causes neurological disorders SMA, ALS FXS. determine axonal dendritic mRNA repertoires well proteomes by trafficking selective regulating local synthesis, play a crucial role function. review, we summarize well-known RBPs, SMN, TDP-43, FUS FMRP, review function synthesis neurons. Furthermore, discuss pathological contribution disorders.

Language: Английский

Citations

95
Recent advances in the nucleolar responses to DNA double-strand breaks DOI Creative Commons
Lea Milling Korsholm, Zita Gál, Blanca Nieto

et al.

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(17), P. 9449 - 9461

Published: Aug. 27, 2020

Abstract DNA damage poses a serious threat to human health and cells therefore continuously monitor repair lesions across the genome. Ribosomal is genomic domain that represents particular challenge due repetitive sequences, high transcriptional activity its localization in nucleolus, where accessibility of factors limited. Recent discoveries have significantly extended our understanding how respond double-strand breaks (DSBs) new kinases multiple down-stream targets been identified. Restructuring nucleolus can occur as consequence DSBs data point an active regulation this process, challenging previous views. Furthermore, insights into coordination cell cycle phases ribosomal argue against existing concepts. In addition, importance nucleolar-DNA response (n-DDR) mechanisms for maintenance genome stability potential such anti-cancer becoming apparent. This review will provide detailed discussion recent findings their implications n-DDR. The n-DDR shares features with (DDR) elsewhere but also emerging independent unique nucleolus.

Language: Английский

Citations

72