Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells DOI Creative Commons
Sofía Nasif, Martino Colombo, Anne‐Christine Uldry

et al.

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(3)

Published: June 9, 2023

Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA pathway with roles in cellular stress responses, differentiation, and viral defense. It functions both quality control post-transcriptional regulation of gene expression. NMD has also emerged as modulator cancer progression, although available evidence supports tumor suppressor pro-tumorigenic role, depending on the model. To further investigate role cancer, we knocked out factor SMG7 HT1080 human fibrosarcoma cell line, resulting suppression function. We then compared oncogenic properties parental SMG7-knockout, rescue line which re-introduced isoforms SMG7. tested effect drug inhibiting SMG1 to distinguish NMD-dependent effects from putative NMD-independent Using cell-based assays mouse xenograft model, showed that function severely compromises phenotype. Molecular analysis revealed strongly reduces matrix metalloprotease 9 (MMP9) expression MMP9 re-expression partially rescues Since promotes migration invasion, metastasis angiogenesis, its downregulation may contribute reduced tumorigenicity NMD-suppressed cells. Collectively, our results highlight potential value inhibition therapeutic approach.

Language: Английский

Nonsense-mediated RNA decay: an emerging modulator of malignancy DOI
Kun Tan, Dwayne G. Stupack, Miles Wilkinson

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(8), P. 437 - 451

Published: May 27, 2022

Language: Английский

Citations

82
Translation‐coupled mRNA quality control mechanisms DOI Creative Commons
Laura Monaghan, Dáša Longman, Javier F. Cáceres

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(19)

Published: Aug. 22, 2023

Abstract mRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into quality control will enable us understand how cellular levels controlled, defective or unwanted mRNAs can be eliminated, dysregulation these contribute human disease. Here we review translation‐coupled mechanisms, including non‐stop no‐go decay pathways, describing their shared trans‐acting factors, differences. We also describe advances in our understanding nonsense‐mediated (NMD) pathway, highlighting recent mechanistic findings, discovery novel as well role NMD physiology its impact on

Language: Английский

Citations

44
Global impact of unproductive splicing on human gene expression DOI Creative Commons
Benjamin Fair, Carlos F. Buen Abad Najar,

Junxing Zhao

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(9), P. 1851 - 1861

Published: Sept. 1, 2024

Language: Английский

Citations

16
The broader sense of nonsense DOI
Evangelos D. Karousis, Oliver Mühlemann

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 47(11), P. 921 - 935

Published: June 29, 2022

Language: Английский

Citations

39
Translation-dependent and -independent mRNA decay occur through mutually exclusive pathways defined by ribosome density during T cell activation DOI Creative Commons

Blandine C. Mercier,

Emmanuel Labaronne, David Cluet

et al.

Genome Research, Journal Year: 2024, Volume and Issue: unknown

Published: March 20, 2024

mRNA translation and decay are tightly interconnected processes both in the context of quality-control pathways for degradation functional mRNAs. Cotranslational through codon usage, ribosome collisions, recruitment specific proteins to ribosomes is an important determinant turnover. However, extent which translation-dependent (TDD) translation-independent (TID) participate mRNAs has not been studied yet. Here we describe a comprehensive analysis basal signal-induced TDD TID mouse primary CD4 + T cells. Our results indicate that most cellular transcripts decayed some manner. further identifies length untranslated regions, density ribosomes, GC3 content as determinants magnitude. Consistently, all undergo changes within their coding sequence upon cell activation display corresponding change level. Moreover, reveal dynamic modulation relationship between activation, with reversal impact GC3- AU3-rich codons. Altogether, our data show strong interconnection mammalian

Language: Английский

Citations

9
A systematic benchmark of Nanopore long-read RNA sequencing for transcript-level analysis in human cell lines DOI Creative Commons
Ying Chen, N. Davidson, Yuk Kei Wan

et al.

Nature Methods, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Abstract The human genome contains instructions to transcribe more than 200,000 RNAs. However, many RNA transcripts are generated from the same gene, resulting in alternative isoforms that highly similar and remain difficult quantify. To evaluate ability study transcript expression, we profiled seven cell lines with five different RNA-sequencing protocols, including short-read cDNA, Nanopore long-read direct RNA, amplification-free cDNA PCR-amplified sequencing, PacBio IsoSeq, multiple spike-in controls, additional transcriptome-wide N 6 -methyladenosine profiling data. We describe differences read length, coverage, throughput reporting sequencing robustly identifies major isoforms. illustrate value of SG-NEx data identify isoforms, novel transcripts, fusion modifications. Together, provide a comprehensive resource enabling development benchmarking computational methods for complex transcriptional events at isoform-level resolution.

Language: Английский

Citations

1
Nanopore sequencing reveals endogenous NMD-targeted isoforms in human cells DOI Creative Commons
Evangelos D. Karousis, Foivos Gypas, Mihaela Zavolan

et al.

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: Aug. 13, 2021

Nonsense-mediated mRNA decay (NMD) is a eukaryotic, translation-dependent degradation pathway that targets mRNAs with premature termination codons and also regulates the expression of some encode full-length proteins. Although many genes express NMD-sensitive transcripts, identifying them based on short-read sequencing data remains challenge.

Language: Английский

Citations

42
Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching DOI Creative Commons
Jennine M. Dawicki-McKenna, Alex J. Félix, Elisa A. Waxman

et al.

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

Published: May 6, 2023

Abstract Alternative splicing of neuronal genes is controlled partly by the coordinated action polypyrimidine tract binding proteins (PTBPs). While PTBP1 ubiquitously expressed, PTBP2 predominantly neuronal. Here, we define footprint in human transcriptome using brain tissue and induced pluripotent stem cell-derived neurons (iPSC-neurons). We map sites, characterize PTBP2-dependent alternative events, identify novel targets including SYNGAP1 , a synaptic gene whose loss-of-function leads to complex neurodevelopmental disorder. find that mRNA promotes nonsense-mediated decay, antisense oligonucleotides (ASOs) disrupt PTBP redirect increase protein expression. In haploinsufficient iPSC-neurons generated from two patients, show PTBP2-targeting ASOs partially restore Our data comprehensively cerebral cortex, guiding development therapeutic tools benefit disorders.

Language: Английский

Citations

20
An improved imaging system that corrects MS2-induced RNA destabilization DOI
Weihan Li, Anna Maekiniemi, Hanae Sato

et al.

Nature Methods, Journal Year: 2022, Volume and Issue: 19(12), P. 1558 - 1562

Published: Nov. 10, 2022

Language: Английский

Citations

27
A comprehensive coverage insurance for cells: revealing links between ribosome collisions, stress responses and mRNA surveillance DOI Creative Commons
Soumasree De, Oliver Mühlemann

RNA Biology, Journal Year: 2022, Volume and Issue: 19(1), P. 609 - 621

Published: May 1, 2022

Cells of metazoans respond to internal and external stressors by activating stress response pathways that aim for re-establishing cellular homoeostasis or, if this cannot be achieved, triggering programmed cell death. Problems during translation, arising from defective mRNAs, tRNAs, ribosomes or protein misfolding, can activate as well mRNA surveillance ribosome quality control programs. Recently, collisions have emerged a central signal translational shown elicit different responses. Here, we review our current knowledge about the intricate mutual connections between collisions, surveillance. A factor connecting sensing collided with degradation nascent polypeptides, dissociation stalled no-go non-stop decay is E3-ligase ZNF598. We tested whether ZNF598 also plays role in nonsense-mediated (NMD) but found it dispensable translation termination-associated pathway, which combination other recent data argues against stable stalling at termination codons being NMD-triggering signal.

Language: Английский

Citations

26