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

被引：5

作者：

Sundararajan, Sanjana ^{[1
]}

Park, Hyewon ^{[1
]}

Kawano, Shinji ^{[2
]}

Johansson, Marnie ^{[3
]}

Lama, Bunu ^{[1
]}

Saito-Fujita, Tomoko ^{[4
]}

Saitoh, Noriko ^{[4
]}

Arnaoutov, Alexei ^{[5
]}

Dasso, Mary ^{[5
]}

Wang, Zhengqiang ^{[6
]}

Keifenheim, Daniel

Clarke, Duncan J. ^{[3
]}

Azuma, Yoshiaki ^{[1
]}

机构：

[1] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA

[2] Okayama Univ Sci, Fac Sci, Dept Biochem, Okayama 7000081, Japan

[3] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA

[4] Canc Inst Japanese Fdn Canc Res, Div Canc Biol, Tokyo 1358550, Japan

[5] Natl Inst Child Hlth & Human Dev, Div Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA

[6] Univ Minnesota, Coll Pharm, Ctr Drug Design, Minneapolis, MN 55455 USA

来源：

ISCIENCE | 2023年 / 26卷 / 05期

关键词：

AURORA B; ALPHA; DNA; ANAPHASE; PICH; IDENTIFICATION; CHROMODOMAIN; BETA; PHOSPHORYLATION; CENTROMERES;

D O I：

10.1016/j.isci.2023.106743

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：24

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