Typologie d'actualités: Team Molecular, Structural and Chemical Biology

A new anticancer therapeutic strategy targeting the protein kinases LIMKs via new innovative chemical compounds

These last years, significant advances have been obtained in oncology leading to an increase of patients’ lifespan and improved life conditions. However, several cancers remain difficult to treat with mitigated results, and more and more resistances are observed. It is then vital to go on developing new therapies.

LIM kinase proteins are overproduced in many cancers and constitute interesting therapeutic targets. All over the world, small chemical molecules targeting their kinase activity have been developed these 15 last years, but failed to reach clinical trial stage. In collaboration with chemists from ICOA Institute, we developed a new category of innovative small molecules, called PROTACs, which aims to decrease or even to totally shut down the production of LIM kinase proteins. Our first results are really promising as 2 of the molecules synthesized by the chemists are very active: they totally shut down LIMK production and exhibit drastic effects on cells. We have to go on with the characterization of these molecules especially their cellular effect to open the path towards a new innovative efficient therapeutic strategy targeting the LIM kinase proteins for cancer treatment.

A new regulatory mechanism involved in the bacterial response to cold shock

Cold shock is a common stress for bacterial pathogens inhabiting warm-blooded hosts. It occurs upon abrupt release from the host into the comparatively cold environment. Understanding how pathogens cope with cold shock is crucial to define how they survive on contaminated surfaces and spread to new hosts.

The‘RNA remodeling’ team and I2BC colleagues discovered that transcription termination factor Rho is a crucial player in the bacterial cold shock response (CSR), challenging the prevalent view that the CSR is mostly a posttranscriptional program. Temperature-sensing mRNA switches either allow (at 37°C) or prevent (at 15°C) Rho-dependent termination of the transcription of cold shock genes. During cold acclimation, the cold shock proteins accumulate until they bind to their mRNAs and switch them back into conformations prone to Rho action, thereby providing negative feedback control of their own expression. This regulatory loop works alongside the established posttanscriptional mechanisms to ensure tight and quick regulation of the cold shock genes.

This discovery published in the journal Molecular Cell illustrates the complexity of the bacterial stress responses and highlights Rho as a promising therapeutic target. It was reported by CNRS Chimie on its website.

Référence :
Rho-dependent transcriptional switches regulate the bacterial response to cold shock
Mildred Delaleau, Nara Figueroa-Bossi, Thuy Duong Do, Patricia Kerboriou, Eric Eveno, Lionello Bossi, & Marc Boudvillain*
Molecular Cell https://doi.org/10.1016/jmolcel.2024.07.034

Protein filaments in the regulation of gene expression

Although every cell in our body contains the same genetic information, cells differ in the way they use it, a process known as “gene expression”. The regulation of gene expression is orchestrated by proteins called transcription factors, which bind to specific sequences within DNA. Transcription factors are traditionally thought to operate mainly as single molecules or dimers.

The article by Mance et al. reveals that several transcription factors of the family known as ZBTB, present in humans and other animals, have the capacity to form non-covalent filamentous structures composed of numerous identical copies of proteins arranged in a chain. At the molecular level, such structures could offer significant advantages for binding to DNA, which is itself an elongated molecule containing numerous repeated sequences. A few examples of filament-forming transcription factors had already been reported, but this study extends the concept to a large family of this protein with important functions. The study - which combines structural, biophysical and functional analysis carried out in vitro and in cells - was carried out by the "Post-translational modifications and DNA repair" team at the CBM and their collaborators in Orléans, Rennes and Marseille, including the "Functional mass spectrometry of molecular assemblies" team also at the CBM.

The findings from this research, together with a complementary study by groups of Benjamin Ebert and Eric Fischer from Dana-Farber Cancer Institute at Harvard (published back-to-back in the same issue of Molecular Cell), challenge the traditional view of transcription factor functionality.

In cells, ZBTB proteins are regulated through a process called SUMOylation, where a small tag called SUMO is added to them, changing how they function. Studies on ZBTB proteins undertaken in Orléans, during which the filamentous structures were discovered, are part of the "SUMOwriteNread" project funded by the European Union (ERC grant no 101078837). Researchers are currently investigating the interplay between the ability to form filaments and SUMO tagging to understand the complex reality of gene expression regulation.

This research was reported by CNRS Chimie on its website.

Dynamic BTB-domain filaments promote clustering of ZBTB proteins.
Lucija Mance, Nicolas Bigot, Edison Zhamungui Sánchez, Franck Coste, Natalia Martín-González, Siham Zentout, Marin Biliškov, Zofia Pukało, Aanchal Mishra, Catherine Chapuis, Ana-Andreea Arteni, Axelle Lateur, Stéphane Goffinont, Virginie Gaudon, Ibtissam Talhaoui, Ignacio Casuso, Martine Beaufour, Norbert Garnier, Franck Artzner, Martine Cadene, Sébastien Huet, Bertrand Castaing & Marcin Józef  Suskiewicz
Molecular Cell 2024
https://doi.org/10.1016/j.molcel.2024.05.029