Stage Master

Description du stage :
In eukaryotes, DNA is made to fit inside the cell nucleus through a high degree of compaction that
is enabled by assembly into chromatin. Processes such as DNA damage repair and transcription
require localized changes in chromatin compaction. Re-organization of nucleosomes to regulate
accessibility is mediated by a set of multi-subunit ATP-dependent chromatin remodeling complexes
that slide or evict nucleosomes from the chromatin fiber. Deregulation of these complexes can
severely impact gene expression, cell identity and genome integrity. Their importance is such that
chromatin remodelling protein mutations are strongly associated to several diseases, including
cancer. Unfortunately, we currently do not understand well enough the molecular details of their
mode of action to be able to translate this into improved medical treatment.
The mammalian SWI/SNF (mSWI/SNF) complex is a chromatin remodeler that comprises a set of
evolutionary conserved ‘core and enzymatic’ subunits, but also ‘auxiliary’ subunits present only in
animals thought to reflect increasing biological complexity. The structure, the molecular details of
interaction and the function of these auxiliary yet important subunits are poorly defined at best. In
our laboratory, we study the structure and function and the of these subunits in health and disease
using cryo-EM and in cell and genomic approaches.
Project available:
Oncology geneticists have accumulated a formidable amount of data linking mSWI/SNF mutations
to cancer cases, yet comparatively little has been done to translate this knowledge into better patient
care. There is accumulating evidence that 3D molecular data on protein interaction interfaces can
play a major role in helping develop therapeutically promising compounds of the short peptide and
peptidomimetic classes. We wish to reveal the three-dimensional structure of auxiliary SWI/SNF
subunits by cryo-EM and x-ray crystallography and elucidate how they interact with the nucleosome and the other core
subunits to understand their mode of recognition of chromatin in health and disease. The
project involves isolating chromatin remodeling complexes from mammalian cells and preparing
new generation high affinity grids to conduct cutting edge cryo-EM studies.