Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease

Sun, Lingling; Mailliot, J.; Schaffitzel, Christiane

doi:10.3390/biomedicines11030722

Cited by 9 publications

(8 citation statements)

References 197 publications

(409 reference statements)

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“…( C ) Schematic of the Octet Bio-Layer Interferometry (BLI) system, using biotin-streptavidin coated surface sensors (1). Sensors were sequentially dipped into wells with 10 nM of 50 nt biotinylated DNA oligonucleotide (2), buffer (3), varying concentrations of UPF1-CH-HD (4), buffer (5), and 2 mM ATP and 50 µM of 51 nt trap strand (not shown for clarity) (6). ( D-E ) Representative BLI traces of UPF1-CH-HD WT ( D ) and I757R ( E ).…”

Section: Resultsmentioning

confidence: 99%

“…Oligonucleotide sequences are provided in Supplementary Table S1. 4 105 and is also made available for use under a CC0 license.…”

Section: In Vitro Transcription and Substrate Annealing For Biochemic...mentioning

confidence: 99%

“…A prototypical example of an mRNA decay pathway that uses a common set of factors to accomplish both transcriptome surveillance and gene expression regulation is nonsense-mediated mRNA decay (NMD) (2). Together, the targets of NMD have been estimated to compose 5-20% of human genes, and defects in NMD are associated with numerous genetic diseases and cancers (3, 4).…”

Section: Introductionmentioning

confidence: 99%

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UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency

Chapman,

Youle,

Grimme

et al. 2023

Preprint

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The RNA helicase UPF1 interacts with mRNAs, mRNA decay machinery, and the terminating ribosome to promote nonsense-mediated mRNA decay (NMD). Structural and biochemical data have revealed that UPF1 exists in an enzymatically autoinhibited “closed” state. Upon binding the NMD protein UPF2, UPF1 undergoes an extensive conformational change into a more enzymatically active “open” state, which exhibits enhanced ATPase and helicase activity. However, mechanically deficient UPF1 mutants can support efficient NMD, bringing into question the roles of UPF1 enzymatic autoinhibition and activation in NMD. Here, we identify two additional important features of the activated open state: slower nucleic acid binding kinetics and enhanced ATP-stimulated nucleic acid dissociation kinetics. Computational modeling based on empirical measurements of UPF1, UPF2, and RNA interaction kinetics predicts that the majority of UPF1-RNA binding and dissociation events in cells occur independently of UPF2 binding. We find that UPF1 mutants with either reduced or accelerated dissociation from RNA have NMD defects, whereas UPF1 mutants that are more dependent on UPF2 for catalytic activity remain active on well-established NMD targets. These findings support a model in which the kinetics of UPF1-mRNA interactions are important determinants of cellular NMD efficiency.

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Section: Resultsmentioning

confidence: 99%

“…Oligonucleotide sequences are provided in Supplementary Table S1. 4 105 and is also made available for use under a CC0 license.…”

Section: In Vitro Transcription and Substrate Annealing For Biochemic...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency

Chapman,

Youle,

Grimme

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The mechanisms by which Upf1 mediates mRNA decay depends on the interacting proteins available, which is determined by the cells’ proliferative and differentiation state ( Z. Sun et al, 2011 ; L. Sun et al, 2023 ). Our data indicate that Upf1–SMG7 interaction is present in PTC-containing mutants but that the interaction is not required for physiological app family expression regulation.…”

Section: Discussionmentioning

confidence: 99%

Fine-Tuning Amyloid Precursor Protein Expression through Nonsense-Mediated mRNA Decay

Rahmati,

Chebli,

Kumar Banote

et al. 2024

eNeuro

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Studies on genetic robustness recently revealed transcriptional adaptation (TA) as a mechanism by which an organism can compensate for genetic mutations through activation of homologous genes. Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (appb)gene, activated TA of two otherappfamily members,appaand amyloid precursor-like protein-2 (aplp2)in zebrafish. The observed transcriptional response ofappaandaplp2required degradation of mutant mRNA and did not depend on Appb protein level. Furthermore, TA between amyloid precursor protein (APP) family members was observed in human neuronal progenitor cells (hNPC), however, compensation was only present during early neuronal differentiation, and could not be detected in a more differentiated neuronal stage or adult zebrafish brain. Using knockdown and chemical inhibition, we showed that nonsense-mediated mRNA decay (NMD) is involved in degradation of mutant mRNA and that Upf1 and Upf2, key proteins in the NMD pathway, regulate the endogenous transcript levels ofappa,appb,aplp1andaplp2. In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizingapp/APPmRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.Significance statementGenetic variations increasing APP levels are associated with Alzheimer's disease (AD) pathophysiology. It is therefore of key interest to understand the mechanisms regulating APP expression levels. Here, we identify transcriptional adaptation as a mechanism by which members of the APP family can modulate the expression level of genes in the same family to compensate for the loss of another. Upon the introduction of a PTC, compensation is driven through factors in the NMD pathway mediating mRNA decay. Interestingly, our data also show that the NMD surveillance machinery is an important aspect of fine-tuning mRNA levels of APP family members even under physiological conditions. Our findings therefore provide insights into compensation between APP members and reveal new targets by which APP can be regulated.

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“…During the process, a number of frameshift mutations may avert from NMD, and probably induce immune reactions [11]. Many previous studies also have indicated that abnormal transcripts which evade from NMD may encode neoantigens potentially triggering immune responses in cancer patients [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel tumor antigens and immune subtypes in breast cancer patients for mRNA vaccine development

Yu,

Liu,

et al. 2024

Preprint

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Background:Breast cancer has overtaken lung cancer as the world's most common malignancy. Despite the development of some mRNA vaccines, no satisfactory vaccination for breast cancer has entered clinical application. Methods:In this study, we used multiple analyses of expression datasets from public sources to find new possible tumor antigens for breast cancer and to hunt for potential treatment-sensitive patients. Results: We identified the antigens DST, ANO6, LAMA3, and NEDD9 as putative candidates. Furthermore, we found five predictive genes to identify specific patients inclined for vaccination, namely TRBC2, CD3D, CD27, CD3E, and TRBV28. Following that, we discovered three immunological subtypes of breast cancer, Cluster 1 and Cluster 3, which were recognized as "cold tumors" with minimal immune activity and were more likely to respond to vaccination. We uncovered that Cluster 1 and Cluster 3 could be further separated into two subgroups, each with distinct immune cell infiltration patterns, suggesting that vaccine responses could differ among these patients. The findings of our study lay theoretical foundation for the development of mRNA vaccine and provide new opportunities for personalized treatment.

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Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease

Cited by 9 publications

References 197 publications

UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency

UPF1 ATPase autoinhibition and activation modulate RNA binding kinetics and NMD efficiency

Fine-Tuning Amyloid Precursor Protein Expression through Nonsense-Mediated mRNA Decay

Identification of novel tumor antigens and immune subtypes in breast cancer patients for mRNA vaccine development

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