3/ Enzymes, environment, molecular pathology

LC BUI, F BUSI, F DESHAYES, JM DUPRET, E PETIT, J RENAULT(Bioprofiler resource), F RODRIGUES LIMA, M VIGUIER

Our aim is to characterise the interactions between xenobiotics and enzymatic pathways at the molecular and functional levels.
Our work focuses mainly on the impact of leukemogenic compounds (benzene, etoposide, etc.) on the tyrosine phosphatase PTPN2, the histone acetyltransferase CREBBP and the histone methyltransferase SETD2.
We are also studying the structural, molecular and functional impact of pathological mutations (notably oncogenes) affecting these enzymes.
PTPN2, CREBBP and SETD2 play a key role in cell signalling and epigenetic processes and have been shown to be involved in normal and malignant haematopoiesis. Using various molecular and cellular approaches, we have established that certain leukemogenic quinone metabolites irreversibly alter the functions of these enzymes. These effects, which result from the covalent modification of cysteines with a catalytic or structural role, have an impact on cell signalling and on the epigenetic modification of histones. In parallel, we have carried out structural and enzymatic approaches that have enabled us to characterise, for the first time, the structure of a pathogenic mutant of PTPN2 (C216G) as well as the functional impact of this mutation.