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Molecular modeling of DNA damage in the nucleosome H/F

This offer is available in the following languages:
Français - Anglais

Date Limite Candidature : jeudi 20 avril 2023

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General information

Reference : UMR8520-NORBEN-004
Nombre de Postes : 1
Date of publication : Friday, January 20, 2023
Scientific Responsible name : Fabrizio CLERI
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 13 February 2023
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

In this thesis at the interface between physics and biology, the successful candidate will develop and build molecular models of nucleosomes carrying damaged DNA sites, and models of repair proteins (UDG and OGG1 glycosylases) by molecular docking, interacting with bent and twisted DNA, such as found in the nucleosome. Molecular dynamics simulations will provide a detailed understanding of the microscopic mechanisms of action of UDG and OGG1, in the context of a single nucleosome, elucidating the role of histone tails and some key modifications of histones. A second part of this joint experimental-theoretical project will focus on the very large-scale molecular dynamics of networks of 3 to 12 polynucleosomes including also DNA defects, and the impact of glycosylases on the local structural rearrangement on these small-scale chromatin subunits.

Work Context

The ANR DYPROSOME project, lasting 4 years, is a combined theoretical and experimental study of the molecular recognition mechanisms by which base excision process (BER) repair proteins identify the first stages of cell damage. DNA in the nucleosome. Our objective is to understand, among others: a) how damaged DNA regions located in nucleosomes are identified by DNA glycosylases; b) the effect that a varying degree of nucleosome compaction has on the access of repair proteins to damaged DNA; c) the intrinsic dynamics of nucleosomes in the process of recognition, movement and rearrangement of DNA in the nucleosome, as well as the involvement of histone cores and tails; d) how the presence of higher order structures, composed of many nucleosomes, affects recognition by glycosylases.
Experiments in biochemistry and cryo-microscopy will complement the molecular simulations and theoretical developments in statistical mechanics. The other teams participating in this project, coordinated by prof. Cleri of the IEMN, are: the Structural and Functional Glycobiology Unit (UGSF Cnrs UMR 8576), Univ LILLE; the Cell Biology and Modeling Laboratory (LBMC Cnrs UMR 5239), ENS Lyon; the Advanced Institute of Biosciences (Cnrs UMR 5309), Univ Grenoble-Alpes.

Constraints and risks

Travel between partner sites, as well as participation in schools, conferences and workshops in France and abroad will be expected.

Additional Information

Profile sought: applicants with a Master's degree in physics, chemistry or biology will be considered. A good attitude towards theoretical developments in biophysics and molecular biology, and computer modeling is important. Programming skills (Fortran, C/C++, Python) constitute a preference requirement. The working language of the group is English; French is not compulsory, but the university program offers free language lessons.
Applications should include: a detailed CV; at least two references (persons likely to be contacted); a one-page cover letter; a one-page summary of the master's thesis; the marks of Master 1 and 2.

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