Biology subjects

Hognon, C.

Publications and source records attributed to Hognon, C..

12 recordsLinked to original sources

bioRxiv2026

The Conformation of the Complementary Strand and the Deformation of the DNA Groove upon DDB2 Binding Justifies the Different Repair Rates for Cyclobutane Pyrimidine Dimers.

The repair of photo-induced DNA lesions through nucleotide excision repair machinery is still the source of important questions. It has been observed that the repair rate of the different cyclobutane pyrimidine dimers, i.e. the photoproducts induced by dimerization of two {pi}-stacked pyrimidines (T<>T, T<>C, C<>T, C<>C), depends on the nucleobases involved in the lesion. TT derivatives (T<>T) are removed more slowly than those containing cytosine, especially in 5. Using all-atom molecular dynamics simulations, we demonstrate that the variation of the repair rate observed in human skin and in cultured cutaneous cell may be associated to the recognition of the four lesions by the DDB2 protein moiety, and more specifically by the differential structural deformation induced on the complementary strand and the major groove. These effects may then hamper differentially the downstream recruitment of the repair complexes. The observed DNA deformation correlates with the experimental repair rate and suggests a structural rationale for the different repair rates of CPD by nucleotide excision repair machinery. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/724087v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1c02e6forg.highwire.dtl.DTLVardef@28b3c1org.highwire.dtl.DTLVardef@3143fborg.highwire.dtl.DTLVardef@664d48_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Influencing Iron Homeostasis by Transition Metal Complexes Interacting with a messenger-RNA Stem Loop in the Iron Regulating Element

The maintaining of the precise regulation of iron homeostasis is fundamental to assure cells viability. In this context the interplay between the messenger RNA Iron Response element (IRE) and the iron response protein 1 (IRP1) is crucial to regulate the expression of ferritin and hence the level of labile free iron pool. We have shown, using a combination of molecular modeling and experimental techniques, that tris bipyridine iron complexes (AIM3) interact specifically with the IRE RNA stem-loop in solution, without inducing noticeable structural deformations. Furthermore, we have also shown that, at a cellular level, this interaction may be traced back to the downregulation of ferritin translation, probably due to the stabilization of the IRE stem-loops thus favoring its binding to IRP1 or by inhibiting the downstream recruitment of ribosomal subunits.

biophysics↗

bioRxiv2023

The dynamics of protein-RNA interfaces using all-atom molecular dynamics simulations

Facing the current challenges raised by human health diseases requires the understanding of cell machinery at a molecular level. The interplay between proteins and RNA is key for any physiological phenomenon, as well protein-RNA interactions. To understand these interactions many experimental techniques have been developed, spanning a very wide range of spatial and temporal resolutions. In particular, the knowledge of tridimensional structures of protein-RNA complexes provides structural, mechanical and dynamical pieces of information essential to understand their functions. To get insights into the dynamics of protein-RNA complexes, we carried out all-atom molecular dynamics simulations in explicit solvent on nine different protein-RNA complexes with different functions and interface size by taking into account the bound and unbound forms. First, we characterized structural changes upon binding and for the RNA part the change in the puckering. Second, we extensively analyzed the in-terfaces, their dynamics and structural properties, and the structural waters involved in the binding, as well as the contacts mediated by them. Based on our analysis, the interfaces rearranged during the simulation time showing alternative and stable residue-residue contacts with respect to the experimental structure.

biochemistry↗

bioRxiv2021

Never cared for what they do. High structural stability of Guanine-quadruplexes in presence of strand-break damages

DNA integrity is an important factor to assure genome stability and, more generally, cells and organisms viability. In presence of DNA damage, the normal cell cycle is perturbed while cells activate their repair processes. Although efficient, the repair system is not always able to ensure the complete restoration of gene integrity. In these cases, not only mutations may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold which induces apoptosis and the programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiations are the most toxic, due to their inherently difficult repair, which may lead to genomic instability. In this article we show, by using classical molecular simulations techniques, that differently from the canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show a remarkable structural stability, even in presence of two strand breaks. Since G4-DNA are recognized for their regulatory roles in cell senescence and gene expression, also involving oncogene, their stability can be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.

biophysics↗

bioRxiv2021

Structural and functional characterization of DdrC, a novel DNA damage-induced nucleoid associated protein involved in DNA compaction

Deinococcus radiodurans is a spherical bacterium well-known for its outstanding resistance to DNA-damaging agents. Exposure to such agents leads to drastic changes in the transcriptome of D. radiodurans. In particular, four Deinococcus-specific genes, known as DNA Damage Response genes, are strongly up-regulated and have been shown to contribute to the resistance phenotype of D. radiodurans. One of these, DdrC, is expressed shortly after exposure to {gamma}-radiation and is rapidly recruited to the nucleoid. In vitro, DdrC has been shown to compact circular DNA, circularize linear DNA, anneal complementary DNA strands and protect DNA from nucleases. To shed light on the possible functions of DdrC in D. radiodurans, we determined the crystal structure of the domain-swapped DdrC dimer at a resolution of 2.2 [A] and further characterized its DNA binding and compaction properties. Notably, we show that DdrC bears two asymmetric DNA binding sites located on either side of the dimer and can modulate the topology and level of compaction of circular DNA. These findings suggest that DdrC may be a DNA damage-induced nucleoid-associated protein that enhances nucleoid compaction to limit the dispersion of the fragmented genome and facilitate DNA repair after exposure to severe DNA damaging conditions.

microbiology↗

bioRxiv2021

The iron maiden. Cytosolic aconitase/IRP1 conformational transition in the regulation of ferritin translation and iron hemostasis

Maintaining iron homeostasis is fundamental for almost all living being, and its deregulation correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn this is regulated by the iron-sensitive conformational equilibrium between aconitase and IRP, mediated by the presence of an iron-sulfur cluster. In this contribution we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA, and the conformational transition. Furthermore, the role of the iron-sulfur cluster in driving the conformational transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations.

biophysics↗

bioRxiv2021

How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

biochemistry↗

bioRxiv2021

Staring at the naked Goddess. Unraveling structure and reactivity of Artemis endonuclease interacting with a DNA double strand.

Artemis is an endonuclease responsible for breaking hairpin DNA strand during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, or the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulation, both classically and at hybrid quantum mechanics/ molecular mechanics level, we evidence the stable interaction modes of Artemis with a model DNA strand. We also analyze the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.

biophysics↗

bioRxiv2021

Structure and dynamics of RNA guanine quadruplexes in SARS-CoV-2 genome. Original strategies against emerging viruses

Guanine quadruplexes (G4) structures in viral genome have a key role in modulating viruses biological activity. While several DNA G4 structures have been experimentally resolved, RNA G4s are definitely less explored. We report the first calculated G4 structure of the RG-1 RNA sequence of SARS-CoV-2 genome, obtained by using a multiscale approach combining quantum and classical molecular modelling and corroborated by the excellent agreement between the corresponding calculated and experimental circular dichroism spectra. We prove the stability of RG-1 G4 arrangement as well as its interaction with G4 ligands potentially inhibiting viral protein translation.

biophysics↗

bioRxiv2020

Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions.

Human telomeric DNA (h-Telo), in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics (MD) simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

biophysics↗

bioRxiv2020

Photoinduced DNA Lesions in Dormant Bacteria. The Peculiar Route Leading to Spore Photoproduct Unraveled by Multiscale Molecular Dynamics

Some bacterial species enter a dormant state in the form of spores to resist to unfavorable external conditions. Spores are resistant to a wide series of stress agents, including UV radiation, and can last for tens to hundreds of years. Due to the suspension of biological functions such as DNA repair, they accumulate DNA damage upon exposure to UV radiation. Differently from active organisms, the most common DNA photoproduct in spores are not cyclobutane pyrimidine dimers, but rather the so-called spore photoproduct. This non-canonical photochemistry results from the dry state of DNA and the binding to small acid soluble proteins that drastically modify the structure and photoreactivity of the nucleic acid. In this contribution, we use multiscale molecular dynamics simulations including extended classical molecular dynamics and QM/MM biased dynamics to elucidate the coupling of electronic and structural factors leading to this photochemical outcome. In particular, we rationalize the well-described impact of the peculiar DNA environment found in spores on the favored formation of the spore photoproduct, given the small free energy barrier found for this path. Meanwhile, the specific organization of spore DNA precludes the photochemical path leading to cyclobutane pyrimidine dimers formation. TOC GRAPHICS O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biophysics↗

bioRxiv2020

Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses

Coronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible of a global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting SARS viruses to bypass the host protective response. This work also constitutes a first step of the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/029447v2_ufig1.gif" ALT="Figure 1"> View larger version (99K): org.highwire.dtl.DTLVardef@1497e69org.highwire.dtl.DTLVardef@a4c44org.highwire.dtl.DTLVardef@1511b7org.highwire.dtl.DTLVardef@13e12c1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗