A new molecular pathway in the response of cancer cells to genotoxic agents
A collaboration between several teams from the GIGA of the University of Liege and the Department of Microbiology and Infectious Diseases of the University of Sherbrooke in Canada has led to the identification of a new molecular pathway involved in the response of cancer cells to genotoxic agents.
In cancer therapy, the success of chemotherapy relies on the induction of a cell death program, specifically triggered in tumor cells following their exposure to chemical agents and allowing their elimination. Cisplatin is a chemotherapeutic agent used to treat many types of cancer, including ovarian and breast cancer. Despite its effectiveness, the recurrent problem with the use of cisplatin is the appearance of resistant cancer cells and sometimes severe side effects. The teams of Dr. Yvette Habraken and Prof. Franck Dequiedt (GIGA-Molecular Biology of Diseases) have identified a new molecular pathway involved in the response of cancer cells to cisplatin. The scientists have shown that following treatment with cisplatin, c-Jun, a molecular factor usually involved in transcription (the first steps in gene expression), also impacts mRNA splicing (an important step during gene expression that defines the final structure of mRNA). Via this new function, c-Jun induces the expression of a short isoform of the mitochondrial enzyme COASY, which is responsible for cisplatin-induced cell death. These discoveries could ultimately contribute to improving the efficacy of genotoxic anticancer treatments and limiting their deleterious effects.
© Adeline Deward - Illumine
Model: Atypical post-transcriptional role of the transcription factor c-Jun.
In the presence of cisplatin, direct interaction between c-Jun and the RNA-binding protein RBM39 is promoted, reducing RBM39 recruitment to pre-messenger RNAs and inducing alternative splicing shaping the cellular stress response.
Left: splicing of COASY dependent on RBM39 leading to a long isoform.
Right: cisplatin-induced alternative splicing of COASY leading to a short isoform whose expression promotes mitochondrial fusion and apoptosis
This study is the result of multiple collaborations between GIGA researchers (Yvette Habraken, Franck Dequiedt, Alain Colige, Olivier Peulen) and the technology platforms (GIGA-Imaging and GIGA-Genomics).
Fundings : ARC of ULiège (Yvette Habraken/Alain Colige), FNRS, Télévie, Fondation Léon Fredericq, Fondation contre le Cancer
The transcription factor c-Jun inhibits RBM39 to reprogram pre-mRNA splicing during genotoxic stress
Florence Lemaitre, Fatima Chakrama, Tina O’Grady, Olivier Peulen, Gilles Rademaker, Adeline Deward, Benoit Chabot, Jacques Piette, Alain Colige, Charles Lambert, Franck Dequiedt, Yvette Habraken