Post-Translational Modifications Orchestrate Repair of Trapped Topoisomerase-Induced DNA Breaks via TDP1 and TDP2.

DNA topoisomerases are critical for maintaining DNA topology and facilitating replication, transcription, and chromatin organization in both nuclear and mitochondrial genomes. When covalently trapped on DNA as topoisomerase cleavage complexes (Topcc's), notably Top1ccs and Top2ccs, these enzymes generate cytotoxic DNA lesions that disrupt genomic integrity and threaten cell viability. Tyrosyl-DNA phosphodiesterase (TDP1 and TDP2) has emerged as key player in the resolution of these lesions, with broader roles in the repair of diverse DNA end structures. Post-translational modifications (PTMs) dynamically regulate the DNA damage response by modulating the activity, localization, and interactions of repair factors. This review provides a comprehensive overview of the mechanisms by which PTMs modulate the activity of Top1 and Top2, and the repair of their covalently trapped complexes. We further delineate how PTMs fine-tune the functional networks of TDP1 and TDP2, enhancing their efficiency in resolving Topccs and preserving genome stability. Together, these insights highlight the multilayered regulatory mechanisms that safeguard genomic integrity and offer potential avenues for therapeutic intervention.