The shaping of mRNA translation plasticity by RNA G-quadruplexes in cancer progression and therapy resistance

Cammas, Anne; Desprairies, Alice; Dassi, Erik; Millevoi, Stefania

doi:10.1093/narcan/zcae025

NAR Cancer

2024

DOI: 10.1093/narcan/zcae025

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The shaping of mRNA translation plasticity by RNA G-quadruplexes in cancer progression and therapy resistance

Anne Cammas,

Alice Desprairies,

Erik Dassi

et al.

Abstract: Translational reprogramming in response to oncogenic signaling or microenvironmental stress factors shapes the proteome of cancer cells, enabling adaptation and phenotypic changes underlying cell plasticity, tumor progression and response to cancer therapy. Among the mechanisms regulating translation are RNA G-quadruplexes (RG4s), non-canonical four-stranded structures whose conformational modulation by small molecule ligands and RNA-binding proteins affects the expression of cancer proteins. Here, we discuss … Show more

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Cited by 3 publications

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“…Cammas et al . focus on how RG4s specifically contribute to the translational reprogramming occurring in cancer cells through paradigmatic examples highlighting their role ( 10 ).…”

mentioning

confidence: 99%

Editorial: Translational control in cancer

Aguilo,

Dassi

2024

NAR Cancer

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“…Cammas et al . focus on how RG4s specifically contribute to the translational reprogramming occurring in cancer cells through paradigmatic examples highlighting their role ( 10 ).…”

mentioning

confidence: 99%

Editorial: Translational control in cancer

Aguilo,

Dassi

2024

NAR Cancer

Self Cite

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A Compendium of G-Flipon Biological Functions That Have Experimental Validation

Herbert

2024

IJMS

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As with all new fields of discovery, work on the biological role of G-quadruplexes (GQs) has produced a number of results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly because they are different from commonly held expectations. Like other classes of flipons, those that form G-quadruplexes have a repeat sequence motif that enables the fold. The canonical DNA motif (G3N1–7)3G3, where N is any nucleotide and G is guanine, is a feature that is under active selection in avian and mammalian genomes. The involvement of G-flipons in genome maintenance traces back to the invertebrate Caenorhabditis elegans and to ancient DNA repair pathways. The role of GQs in transcription is supported by the observation that yeast Rap1 protein binds both B-DNA, in a sequence-specific manner, and GQs, in a structure-specific manner, through the same helix. Other sequence-specific transcription factors (TFs) also engage both conformations to actuate cellular transactions. Noncoding RNAs can also modulate GQ formation in a sequence-specific manner and engage the same cellular machinery as localized by TFs, linking the ancient RNA world with the modern protein world. The coevolution of noncoding RNAs and sequence-specific proteins is supported by studies of early embryonic development, where the transient formation of G-quadruplexes coordinates the epigenetic specification of cell fate.

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A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

Neidle

2024

Molecules

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G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer.

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The shaping of mRNA translation plasticity by RNA G-quadruplexes in cancer progression and therapy resistance

Cited by 3 publications

References 51 publications

Editorial: Translational control in cancer

Editorial: Translational control in cancer

A Compendium of G-Flipon Biological Functions That Have Experimental Validation

A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs

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