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Methylated histones on mitotic chromosomes promote topoisomerase IIα function for high fidelity chromosome segregation
Sundararajan, Sanjana Park, Hyewon Kawano, Shinji Johansson, Marnie Lama, Bunu Saito-Fujita, Tomoko Saitoh, Noriko Arnaoutov, Alexei Dasso, Mary Wang, Zhengqiang
Sundararajan, Sanjana
Park, Hyewon
Kawano, Shinji
Johansson, Marnie
Lama, Bunu
Saito-Fujita, Tomoko
Saitoh, Noriko
Arnaoutov, Alexei
Dasso, Mary
Wang, Zhengqiang
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Abstract
DNA Topoisomerase IIα (TopoIIα) decatenates sister chromatids, allowing their segregation in mitosis. Without the TopoIIα Strand Passage Reaction (SPR), chromosome bridges and ultra-fine DNA bridges (UFBs) arise in anaphase. The TopoIIα 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 αChT residues disrupts αChT-nucleosome interaction, induces loss of segregation fidelity and reduces association of TopoIIα with chromosomes. Specific methyltransferase inhibitors reducing histone H3 or H4 methylation decreased TopoIIα at centromeres 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 TopoIIα specifically interacts with methylated nucleosomes via the αChT to ensure high-fidelity chromosome segregation.
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Date
2023-05-19
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Publisher
Cell Press
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Keywords
Biological sciences, Molecular biology, Chromosome organization, Molecular mechanism of gene regulation
Citation
Sundararajan, S., Park, H., Kawano, S., Johansson, M., Lama, B., Saito-Fujita, T., Saitoh, N., Arnaoutov, A., Dasso, M., Wang, Z., Keifenheim, D., Clarke, D. J., & Azuma, Y. (2023). Methylated histones on mitotic chromosomes promote topoisomerase IIα function for high fidelity chromosome segregation. iScience, 26(5), 106743. https://doi.org/10.1016/j.isci.2023.106743