Structural and Functional Studies of Human Type II Topoisomerases and their Post-Translational Modifications
Abstract
Type II DNA Topoisomerases (Top2) are essential enzymes involved in DNA replication, DNA condensation and chromosome segregation. They remove topological stress that appear in the DNA duplex by releasing catenates, relaxing supercoils and removing knots through transient double strand breaks. This mechanism is currently targeted by compounds used in cancer chemotherapy, that prevent religation of DNA breaks and lead to cell death. The implication of these enzymes in the cell cycle raises the question of their regulation notably by post-translational modifications (PTM). Anti-cancer drugs such as doxorubicin and etoposide were shown to induce hyperphosphorylation or hypophosphorylation in cancer cells. However the role of PTM in the catalytic regulation of Top2 is not clearly understood.In this work, we have focused on the post-translational modifications of the human Top2. We have systematically identified the phosphorylation and acetylation sites in the Top2 isoforms, and observed a distinct distribution of both modifications. This identification allowed us to understand the role of a catalytic residue subject to an acetylation and the potential impact of this modification.