CE12 - Génétique, génomique et ARN

Assembly of macromolecular complexes by HSP90/R2TP – YMCR

Submission summary

The assembly of macromolecular complexes is an essential cellular process. It often requires chaperones and dedicated co-factors to facilitate tertiary and quaternary folding. The HSP90/R2TP chaperone plays a unique role in this process, as a generalist assembly machine that generates multi-subunit protein and protein-RNA complexes. The R2TP consists of a RPAP3:PIH1D1 hetero-dimer associated with a hetero-hexamer of the AAA+ ATPases RUVBL1 and RUVBL2. In the recent years, our consortium, together with other laboratories, has shown that the R2TP is involved in the assembly of a large number of macromolecular complexes, including many non-coding RNPs (snRNPs, snoRNPs, miRNPs and the telomerase RNP), the nuclear RNA polymerases and the kinases of the PIKK family. Overall, it is estimated that the R2TP chaperone is involved in the assembly of about a hundred client complexes. Despite these advances, the assembly mechanism used by R2TP still remains incompletely characterized. By harnessing the complementary expertises of our consortium, this project will address three important questions:
1. What are the co-translational events occurring during R2TP-mediated complex assembly ?
2. What is the assembly mechanism used by HSP90/R2TP ?
3. What are the roles of HSP90/R2TP during proteotoxic stresses ?

To address these questions, we will rely on a series of innovative approaches ranging from in vivo genome-wide studies to in vitro biochemical and structural experiments on C/D snoRNPs. Our consortium has a strong interdisciplinary culture, bringing together experts in advanced imaging, RNA molecular biology, next-generation proteomics, biophysics and structural biology. This ambitious project addresses an essential but poorly studied question. It will provide a multiscale, integrated view of how the assembly of macromolecular complexes occurs in the cell, an essential process that shapes the cellular interactome.

Project coordination

Edouard Bertrand (Institut de Génétique Humaine)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LBMCE Biologie moléculaire et cellulaire des eucaryotes
IGH Institut de Génétique Humaine
IMoPA Ingénierie Moléculaire et Physiopathologie Articulaire
MCD Unité de biologie moléculaire, cellulaire et du développement
IPHC Institut Pluridisciplinaire Hubert Curien - IPHC (UMR 7178)

Help of the ANR 740,246 euros
Beginning and duration of the scientific project: September 2023 - 48 Months

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