Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Pawlicka, Kamila; Kalathiya, Umesh; Alfaro, Javier A.

doi:10.3390/cancers12030765

Cited by 39 publications

(29 citation statements)

References 111 publications

(146 reference statements)

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“…However, NMD can control the quality of mRNA by eliminating PTC-containing mRNA ( 17 , 51 ). Therefore, NMD inhibitors are considered a novel treatment strategy against various diseases ( 52 ). Since EIF4A3 plays a key role in NMD, EIF4A3-targeted strategies may open a new path for treating cancer and other PTC-related genetic diseases.…”

Section: Eif4a3 As a Therapeutic Targetmentioning

confidence: 99%

Eukaryotic Initiation Factor 4A-3: A Review of Its Physiological Role and Involvement in Oncogenesis

She

Liu

et al. 2021

Front. Oncol.

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EIF4A3, a member of the DEAD-box protein family, is a nuclear matrix protein and a core component of the exon junction complex (EJC). Under physiological conditions, EIF4A3 participates in post-transcriptional gene regulation by promoting EJC control of precursor mRNA splicing, thus influencing nonsense-mediated mRNA decay. In addition, EIF4A3 maintains the expression of significant selenoproteins, including phospholipid hydroperoxide glutathione peroxidase and thioredoxin reductase 1. Several recent studies have shown that EIF4A3 promotes tumor growth in multiple human cancers such as glioblastoma, hepatocellular carcinoma, pancreatic cancer, and ovarian cancer. Molecular biology studies also showed that EIF4A3 is recruited by long non-coding RNAs to regulate the expression of certain proteins in tumors. However, its tumor-related functions and underlying mechanisms are not well understood. Here, we review the physiological role of EIF4A3 and the potential association between EIF4A3 overexpression and tumorigenesis. We also evaluate the protein’s potential utility as a diagnosis biomarker, therapeutic target, and prognosis indicator, hoping to provide new ideas for future research.

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Section: Eif4a3 As a Therapeutic Targetmentioning

confidence: 99%

Eukaryotic Initiation Factor 4A-3: A Review of Its Physiological Role and Involvement in Oncogenesis

She

Liu

et al. 2021

Front. Oncol.

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“…It may result in an alternative protein sequence with functions that can be different, and sometimes opposite to those translated from the canonical transcript. Alternatively, the transcript may be targeted for nonsense-mediated mRNA decay (NMD) if a STOP codon is introduced, thus resulting in a downregulation of the protein expression [ 37 ]. A strict regulation is necessary to control different splicing patterns characteristic of cell type and maturation stage [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Hautin

Mornet

Chauveau

et al. 2020

Cancers

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Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

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“…Recent advances in molecular and cell biology present an alternative therapeutic opportunity to counter the genetic defects (PTC mutations) by pharmacological modulation (NMD or proteasomal degradation inhibitors) and help to control disease pathogenesis (54,57,58). In theory, HoFH patients who are unresponsive to statins might benefit from the use of pharmacological modulators like aminoglycosides in restoring partial sized LDLR molecules arising from stop gain mutations.…”

Section: Discussionmentioning

confidence: 99%

Saudi Familial Hypercholesterolemia Patients With Rare LDLR Stop Gain Variant Showed Variable Clinical Phenotype and Resistance to Multiple Drug Regimen

et al. 2021

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Familial hypercholesterolemia (FH), a well-known lipid disease caused by inherited genetic defects in cholesterol uptake and metabolism is underdiagnosed in many countries including Saudi Arabia. The present study aims to identify the molecular basis of severe clinical manifestations of FH patients from unrelated Saudi consanguineous families. Two Saudi families with multiple FH patients fulfilling the combined FH diagnostic criteria of Simon Broome Register, and the Dutch Lipid Clinic Network (DLCN) were recruited. LipidSeq, a targeted resequencing panel for monogenic dyslipidemias, was used to identify causative pathogenic mutation in these two families and in 92 unrelated FH cases. Twelve FH patients from two unrelated families were sharing a very rare, pathogenic and founder LDLR stop gain mutation i.e., c.2027delG (p.Gly676Alafs*33) in both the homozygous or heterozygous states, but not in unrelated patients. Based on the variant zygosity, a marked phenotypic heterogeneity in terms of LDL-C levels, clinical presentations and resistance to anti-lipid treatment regimen (ACE inhibitors, β-blockers, ezetimibe, statins) of the FH patients was observed. This loss-of-function mutation is predicted to alter the free energy dynamics of the transcribed RNA, leading to its instability. Protein structural mapping has predicted that this non-sense mutation eliminates key functional domains in LDLR, which are essential for the receptor recycling and LDL particle binding. In conclusion, by combining genetics and structural bioinformatics approaches, this study identified and characterized a very rare FH causative LDLR pathogenic variant determining both clinical presentation and resistance to anti-lipid drug treatment.

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Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Cited by 39 publications

References 111 publications

Eukaryotic Initiation Factor 4A-3: A Review of Its Physiological Role and Involvement in Oncogenesis

Eukaryotic Initiation Factor 4A-3: A Review of Its Physiological Role and Involvement in Oncogenesis

Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Saudi Familial Hypercholesterolemia Patients With Rare LDLR Stop Gain Variant Showed Variable Clinical Phenotype and Resistance to Multiple Drug Regimen

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