Methylated histones on mitotic chromosomes promote topoisomerase IIα function for high fidelity chromosome segregation
Sanjana Sundararajan,
Hyewon Park,
Shinji Kawano,
Marnie Johansson,
Bunu Lama,
Tomoko Saito-Fujita,
Noriko Saitoh,
Alexei Arnaoutov,
Mary Dasso,
Zhengqiang Wang,
Daniel Keifenheim,
Duncan J. Clarke,
Yoshiaki Azuma
Affiliations
Sanjana Sundararajan
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
Hyewon Park
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
Shinji Kawano
Department of Biochemistry, Faculty of Science, Okayama University of Science, Okayama 700-0081, Japan
Marnie Johansson
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Bunu Lama
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
Tomoko Saito-Fujita
Division of Cancer Biology, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Noriko Saitoh
Division of Cancer Biology, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Alexei Arnaoutov
Division of Molecular and Cellular Biology, National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4480, USA
Mary Dasso
Division of Molecular and Cellular Biology, National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4480, USA
Zhengqiang Wang
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Daniel Keifenheim
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Duncan J. Clarke
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Yoshiaki Azuma
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA; Corresponding author
Summary: 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.
