Biology subjects

Monchaud, D.

Publications and source records attributed to Monchaud, D..

7 recordsLinked to original sources

bioRxiv2026

The DNA damaging properties of the experimental G-quadruplex (G4) drug QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC

BackgroundQN-302 is a tetra-substituted naphthalene diimide (NDI) compound designed to interact with G-quadruplex (G4) DNA. QN-302 is currently being evaluated in a phase 1 clinical trial on patients with advanced pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. However, the mechanistic origin(s) of its anticancer activity remains to be fully understood. ResultsWe report herein the ability of QN-302 to damage DNA at G4 sites in cancer cells. To this end, we implemented a series of in vitro assays (FQA and FRET-melting) and cell-based techniques (in situ click imaging and immunodetection) that concurred in demonstrating both the DNA damaging properties of QN-302 and its ability to engage G4s in human cancer cells. Then, we investigate its anticancer effects in PDAC (MIA PaCa-2 cells) and show that it can be efficiently potentiated upon combination with Olaparib, an inhibitor of DNA repair, in an approach referred to as chemically induced synthetic lethality. ConclusionThis study not only confirms the excellent anticancer properties of QN-302 in human cancer cells but also provides insights into its mechanism of action. The optimization of this therapeutic activity by combination with Olaparib opens a promising new avenue for improving its clinical efficacy.

cancer biology↗

bioRxiv2024

G-quadruplex formation in long non-coding RNAs dysregulated in colorectal cancer

Non-coding RNAs (ncRNAs) in human cells do not lead to protein synthesis and constitute a substantial portion of the transcriptome. Human long non-coding RNAs (lncRNAs) orchestrate critical cellular functions influencing development, differentiation, and metabolism. Dysregulation of lncRNAs has been correlated with several pathological conditions such as neurodegenerative and autoimmune disorders, diabetes, and cancer. Recent reports have suggested the involvement of G4s in lncRNAs to regulate colorectal cancer (CRC) carcinogenesis. In this study, we investigate the occurrence and distribution of G4s in the LINC01589, MELTF-AS1, and UXT-AS1 lncRNAs, which have been reported to be dysregulated in CRC. Using a combination of in silico tools and in vitro biophysical techniques, we show that these lncRNAs form stable, parallel, and intramolecular G4s. Furthermore, we establish the formation of G4s within these lncRNAs in CRC using cell-based assays, including RNA G4-Immuno-FISH and G4RP-RT-qPCR. This is the first systematic study of G4s in lncRNAs dysregulated in CRC, and our findings highlight the diagnostic and therapeutic potential of G4s in CRC.

biochemistry↗

bioRxiv2024

Small-molecule-based regulation of gene expression in human astrocytes upon both positive and negative actuations of G-quadruplex control systems

A great deal of attention is currently being paid to strategies aiming at uncovering the biology of the four-stranded nucleic acid structure G-quadruplex (G4) via their stabilization in cells using G4-specific ligands. The conventional definition of chemical biology implies that a complete assessment of G4 biology can only be achieved through the implementation of a complementary approach involving the destabilization of cellular G4s by ad hoc molecular effectors. We report here on an unprecedented comparison of the cellular consequences of G4 chemical stabilization by pyridostatin (PDS) and destabilization by phenylpyrrolocytosine (PhpC) at both transcriptome- and proteome-wide scales in patient-derived human brain cells. Our results show that the stabilization of G4s by PDS triggers the dysregulation of many cellular circuitries, the most drastic effects originating in the downregulation of 354 transcripts and 158 proteins primarily involved in RNA transactions. In contrast, the destabilization of G4s by PhpC modulates the G4 landscapes in a far more focused manner with the upregulation of 295 proteins mostly involved in RNA transactions as well, thus mirroring the effects of PDS. Our study is the first of its kind to report on the extent of G4-associated cellular circuitries in human cells by systematically pitting the effect of G4 stabilization against destabilization in a direct and unbiased manner.

genetics↗

bioRxiv2024

RNA G-quadruplex dynamic steers the crosstalk between protein synthesis and energy metabolism

Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.

cancer biology↗

bioRxiv2022

The multivalent G-quadruplex (G4)-ligands MultiTASQs allow for versatile click chemistry-based investigations

Chemical biology hinges on multivalent molecular tools that uniquely allow for interrogating and/or manipulating cellular circuitries from the inside. The success of many of these approaches relies on molecular tools that make it possible to visualize biological targets in cells and then isolate them for identification purposes. To this end, click chemistry has become in just a few years a vital tool in offering practically convenient solutions to address highly complicated biological question. We report here on two clickable molecular tools, the biomimetic G-quadruplex (G4) ligands MultiTASQ and azMultiTASQ, which benefit from the versatility of two types of bioorthogonal chemistry, CuAAC and SPAAC (the discovery of which was very recently awarded the Nobel Prize of chemistry). These two MultiTASQs are here used to both visualize G4s in, and identify G4s from human cells. To this end, we developed click chemo-precipitation of G-quadruplexes (G4-click-CP) and in situ G4 click imaging protocols, which provide unique insights into G4 biology in a straightforward and reliable manner.

genetics↗

bioRxiv2020

Biomimetic, smart and multivalent ligands for G-quadruplex isolation and bioorthogonal imaging

G-quadruplexes (G4s) continue to gather wide attention in the field of chemical biology as their prevalence in the human genome and transcriptome strongly suggests that they may play key regulatory roles in cell biology. G4-specific, cell-permeable small molecules (G4-ligands) innovately permit the interrogation of cellular circuitries in order to assess to what extent G4s influence cell fate and functions. Here, we report on multivalent, biomimetic G4-ligands referred to as TASQs that enable both the isolation and visualization of G4s in human cells. Two biotinylated TASQs, BioTASQ and BioCyTASQ, are indeed efficient molecular tools to fish out G4s of mixtures of nucleic acids through simple affinity capture protocols and to image G4s in cells via a biotin/avidin pretargeted imaging system first applied here to G4s, found to be a reliable alternative to in situ click chemistry. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/422878v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@2db02dorg.highwire.dtl.DTLVardef@1897e59org.highwire.dtl.DTLVardef@1c63716org.highwire.dtl.DTLVardef@4a8a5d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2020

Disclosing the actual efficiency of G-quadruplex DNA-disrupting small molecules

The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to i- screen or design G4-ligands, ii- evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and iii- use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort to i- develop a reliable in vitro assay to identify molecules able to destabilize G4s, the G4-unfold assay, and ii- fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog.

biophysics↗