Olivia Vidal-Cruchez

Institut de Recherche sur le Cancer et le Vieillissement de Nice

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Karine Jacquet

Université Claude Bernard Lyon 1

Victoria J. Nicolini

Inserm

Patrick Brest

Université Côte d'Azur

Bernard Mari

Inserm

Baharia Mograbi

Université Côte d'Azur

Roger Rezzonico

Inserm

Paul Hofman

Institut de Recherche sur le Cancer et le Vieillissement de Nice

Arnaud Hubstenberger

Inserm

Tifenn Rete

Centre Antoine Lacassagne

Jérémie Roux

Institut de Pharmacologie Moléculaire et Cellulaire

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Centre National de la Recherche Scientifique

Université Côte d'Azur

Inserm

Institut de Recherche sur le Cancer et le Vieillissement de Nice

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Centre Antoine Lacassagne

Observatoire de la Côte d’Azur

Institut de Pharmacologie Moléculaire et Cellulaire

Centre Hospitalier Universitaire de Nice

Université Claude Bernard Lyon 1

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New technologies for improved relevance in miRNA research

Trends in Genetics (2021)

Karine Jacquet Olivia Vidal-Cruchez Roger Rezzonico Victoria J. Nicolini Baharia Mograbi

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10.1016/j.tig.2021.08.006

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Citations (14)

KRAS and NRAS Translation Is Increased upon MEK Inhibitors-Induced Processing Bodies Dissolution

Cancers (2023)

Olivia Vidal-Cruchez Victoria J. Nicolini Tifenn Rete Karine Jacquet Roger Rezzonico

Overactivation of the mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies directly targeting this pathway lead to cancer drug resistance. Resistance has been linked to compensatory RAS overexpression, but the mechanisms underlying this response remain unclear. Here, we find that MEK inhibitors (MEKi) are associated with an increased translation of the KRAS and NRAS oncogenes through a mechanism involving dissolution of processing body (P-body) biocondensates. This effect is seen across different cell types and is extremely dynamic since removal of MEKi and ERK reactivation result in reappearance of P-bodies and reduced RAS-dependent signaling. Moreover, we find that P-body scaffold protein levels negatively impact RAS expression. Overall, we describe a new feedback loop mechanism involving biocondensates such as P-bodies in the translational regulation of RAS proteins and MAPK signaling.

HRAS

10.3390/cancers15123078

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Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Olivia Vidal-Cruchez Victoria J. Nicolini Tifenn Rete Roger Rezzonico Caroline Lacoux

Abstract Overactivation of the Mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies targeting this pathway have proven effective in only a few cancers, as cancers inevitably develop resistance. Puzzling observations suggest that MAPK targeting fails in tumors due to early compensatory RAS overexpression, albeit by unexplained mechanisms. We identified a novel mechanism of drug tolerance to MEK inhibitors (MEKi) that involves Processing Bodies (PBs), a membraneless organelle (MLO). MEKi promoted translation of the oncogenes KRAS and NRAS, which in turn triggered BRAF phosphorylation. This overexpression, which occurred in the absence of neotranscription, depended on PB dissolution as the source of the RAS mRNA. Moreover, in response to MEKi removal, the process was dynamic as PBs rapidly reformed and reduced MAPK signaling. These results highlight a dynamic spatiotemporal negative feedback loop of MAPK signaling via RAS mRNA sequestration. Furthermore, we observed a phenotype with a low number of PBs along with strong KRAS and NRAS induction capacities. Overall, we describe a new intricate mechanism involving PBs in the translational regulation of essential cellular signaling pathways like MAPKs, paving the way for future therapies altering MLO and thereby improving targeted cancer therapies.

10.1101/2021.12.06.471470

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Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site

Cells (2024)

Claire Ghilain Olivia Vidal-Cruchez Aurélia Joly Michelle Debatisse Eric Gilson

Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site.

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Nucleoid

10.3390/cells13161361

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