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PhD project on mechanisms regulating the expansion of DNA loops by the cohesin complex

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

Date Limite Candidature : lundi 12 décembre 2022

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General information

Reference : UMR5077-FREBEC-001
Workplace : TOULOUSE
Date of publication : Monday, November 21, 2022
Scientific Responsible name : Frederic BECKOUET
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 2 January 2023
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

We are looking for a highly motivated PhD student to work on the molecular mechanisms involved in DNA loop expansion by the cohesin complex.Cohesin is complex ring-shaped holocomplex with ATPase activity that belongs to the Structural Maintenance Complex (SMC) family. In addition to conferring sister chromatid cohesion, cohesin complexes have the ability to generate distant intrachromosomal loci in the genome of different organisms. These cis chromosomal contacts result in the establishment of large chromatin loops along mammalian interphase chromosome. These cohesin dependent loops contribute to the segmentation of chromosomes into self-interacting topologically associating domains (TADs). The roles of cohesin dependent-loops and TADs in regulating chromosome biological processes such as gene transcription, DNA replication and double-strand break repair are actively investigated. We and others recently discovered that cohesin also organizes yeast mitotic chromosomes into loops, through regulatory pathways similar to those found in mammalian cells.
The molecular mechanisms that regulate the formation and extension of cohesin-dependent DNA loops are actively investigated both in vivo and in vitro. A model proposes that cohesin organise DNA by capturing small loops and extrusion of such loops leads to their processive enlargement, up to megabase sized structures, until encountering physical roadblocks along the DNA or being spontaneously released. Recent biochemical experiments gave strong support to this model by showing that purify cohesins can indeed extrudes DNA loop in ATP dependent manner. Nevertheless, the way that cohesin captures and expand DNA remains debated.
We recently showed that the stimulation of cohesin ATP hydrolysis by Scc2, a cohesin partner involved in DNA loading, play a key role in expanding DNA loop in vivo. Moreover, our study showed that acetylation of cohesin inhibits loop expansion mediated Scc2. However, the mechanism by which acetylation inhibits loop expansion remains mysterious. Therefore, we are looking for a highly motivated PhD student to develop a reconstituted in vitro system to decipher how Smc3 acetylation controls ATPase activity and loop formation.

Work Context

Unité de biologie Moléculaire, Cellulaire et du Développement (MCD), CBI, Université Paul Sabatier de Toulouse

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