Methylated histones on mitotic chromosomes promote topoisomerase IIa function for high fidelity chromosome segregation

DNA Topoisomerase IIa (TopoIIa) decatenates sister chromatids, allowing their segregation in mitosis. Without the TopoIIa Strand Passage Reaction (SPR), chromosome bridges and ultra-fine DNA bridges (UFBs) arise in anaphase. The TopoIIa C-terminal domain is dispensable for the SPR in vitro but essential for mitotic functions in vivo. Here, we present evidence that the Chromatin Tether (ChT) within the CTD interacts with specific methylated nucleosomes and is crucial for high-fidelity chromosome segregation. Mutation of individual aChT residues disrupts aChT-nucleosome interaction, induces loss of segregation fidelity and reduces association of TopoIIa with chromosomes. Specific methyltransferase inhibitors reducing histone H3 or H4 methylation decreased TopoIIa at centro-meres and increased segregation errors. Methyltransferase inhibition did not further increase aberrant anaphases in the ChT mutants, indicating a functional connection. The evidence reveals novel cellular regulation whereby TopoIIa specifically interacts with methylated nucleosomes via the aChT to ensure high-fi-delity chromosome segregation.