Selection and Studies of Antibodies Targeted

Il y a 2 mois

Grenoble, France Département de Chimie Moléculaire (equipe I2BM) Laboratoire Interdisciplinaire de physique (équipe Temps plein

**SELECTION AND STUDIES OF ANTIBODIES TARGETED I-MOTIF DNA**:

- Réf **ABG-119921**
- Sujet de Thèse- 02/02/2024- Contrat doctoral- Département de Chimie Moléculaire (equipe I2BM) / Laboratoire Interdisciplinaire de physique (équipe BIOP)- Lieu de travail- Grenoble - Auvergne-Rhône-Alpes - France- Intitulé du sujet- SELECTION AND STUDIES OF ANTIBODIES TARGETED I-MOTIF DNA- Champs scientifiques- Biotechnologie
- Biochimie
- Biologie
- Mots clés- Phage display, Surface Plasmon Resonance, molecular engineering, biotechnology, microfluidic system, antibody**Description du sujet**:
Les principaux objectifs du travail de thèse sont de sélectionner par la technique phage display des anticorps spécifiques d'unestructure particulière de l'ADN (le i-motif) en utilisant des outils chimiques innovants (i-motif contraints) et de les étudier in vitro.
Les i-motifs sont des structures d'ADN à quatre brins dans lesquelles les cytosines sont intercalées grâce à un empilement de paires debases C-C hémi-protonées (CH+:C), et peuvent se former au niveau de régions riches en C dans les promoteurs et dans les télomères(extrémité des chromosomes). Une particularité de cet ADN i-motif est la forte dépendance de leur formation au pH. En effet, ils sontgénéralement formés in vitro à pH acide (autour de pH = 5), ce qui a remis en cause leur existence dans les cellules. Toutefois desétudes récentes par RMN in cellulo ont montré que ces ADN i-motif serait stables dans les cellules.
Récemment un anticorps (iMab) a été décrit et utilisé pour mettre en évidence par immunofluorescence l’existence de la structure i-motif dans les cellules humaines. Toutefois, la détection de l'ADN i-motif par cet anticorps est très discutable car il n'est pas clair si celui-ci reconnait exclusivement les structures ADN i-motif ou des séquences ADN simples brins riches en cytosine. Les conditions acidesnécessaires pour induire in vitro la formation d'ADN i-motif pourraient conduire à la protonation du ligand (par exemple l'anticorps) etaugmenter ainsi les interactions non spécifiques avec l'ADN. Dans ce contexte en collaboration avec l’Institut Curie d’Orsay, nous avonsrécemment démontré que cet anticorps (iMab) commercial n'est pas spécifique de l'ADN i-motif mais se lie également à des séquencessimples brins riches en cytosine.
Cette remise en compte de la spécificité de l'anticorps iMab commercial démontre la forte nécessité de sélectionner des anticorpscapables de reconnaître plus spécifiquement la conformation repliée du i-motif. Cet anticorps pourrait ensuite être utilisé afin de mieuxcomprendre la fonction de ces ADN i-motif dans les cellules.The principal aims of this work are to use phage display to select antibodies specific for a particular DNA motif (the i-motif) usinginnovative chemical means (constrained i-motif) and to screen them in vitro.
i-motifs are four-stranded DNA structures in which cytosines are interspersed with a stack of hemi-protonated C-C base pairs (CH+:C)and can form at C-rich regions in promoters and telomeres (chromosome ends). A particular feature of i-motif DNA is its strong pHdependence. They generally form in vitro at acidic pH (around pH=5), which has questioned their existence in cells. However, recent in-cell NMR studies have shown that these i-motif DNAs are stable in cells.
Recently, an antibody (iMab) has been described and used to demonstrate the existence of the i-motif structure in human cells byimmunofluorescence. However, the detection of i-motif DNA by this antibody is highly controversial because it is not clear whether it onlyrecognises i-motif DNA structures or single-stranded DNA sequences rich in cytosine. The acidic conditions required to induce i-motifDNA formation in vitro could lead to protonation of the ligand (e.g. the antibody) and thus increase non-specific interactions with DNA. Inthis context, we have recently shown, in collaboration with the Institut Curie in Orsay, that this commercial antibody (iMab) is not specificfor i-motif DNA but also binds to cytosine-rich single-stranded sequences.
This reconsideration of the specificity of the commercial iMab antibody highlights the need to select antibodies capable of morespecifically recognising the folded conformation of the i-motif. This antibody could then be used to better understand the function ofthese i-motif DNAs in cells.

**Nature du financement**:

- Contrat doctoral**Précisions sur le financement**:
**Présentation établissement et labo d'accueil**:

- Département de Chimie Moléculaire (equipe I2BM) / Laboratoire Interdisciplinaire de physique (équipe BIOP)**Etablissement délivrant le doctorat**:

- UNIVERSITE GRENOBLE ALPESThe person recruited must have skills and motivation in microbiology, bacterial culture, molecular biology and protein biochemistry. S/he will be required to maintain a scientific and technological bibliography and to participate in the exploit

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