Disease-associated H58Y mutation affects the nuclear dynamics of human DNA topoisomerase IIβ.
Disease-associated H58Y mutation affects the nuclear dynamics of human DNA topoisomerase IIβ.
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DOI：
10.1038/s41598-022-24883-2
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发表时间：
2022-11-30
影响因子：
4.6
通讯作者：
Yano KI
中科院分区：
文献类型：
--
作者：
Morotomi-Yano K;Hiromoto Y;Higaki T;Yano KI
DNA拓扑异构酶II（TOP2）是一种解决DNA拓扑问题的酶，在各种核过程中起着关键作用。最近，一个杂合H58 Y取代在ATP酶结构域的人TOP 2B被确定为自闭症谱系障碍患者，但其生物学意义尚不清楚。在本研究中，我们分析了TOP 2B与H58 Y（TOP 2B H58 Y）的核动力学。尽管野生型TOP 2 B在活细胞的细胞核中是高度移动的，但TOP 2 B H58 Y的细胞核移动性显著降低，表明H58 Y的影响表现为低蛋白质移动性。我们发现，TOP 2B H58 Y对ICRF-187不敏感，ICRF-187是一种TOP2抑制剂，可阻止TOP2作为DNA上的闭合钳。当TOP 2B的ATP酶活性受损时，TOP 2B H58 Y的核迁移率恢复到野生型水平，表明ATP酶活性对低核迁移率的贡献。对含有TOP 2B H58 Y的基因组编辑细胞的分析表明，TOP 2B H58 Y保留了对TOP2毒物依托泊苷的敏感性，这意味着TOP 2B H58 Y可以进行至少一部分催化反应。总的来说，TOP2 H58 Y代表了疾病相关突变和扰动蛋白质动力学之间关系的一个独特例子。
DNA topoisomerase II (TOP2) is an enzyme that resolves DNA topological problems and plays critical roles in various nuclear processes. Recently, a heterozygous H58Y substitution in the ATPase domain of human TOP2B was identified from patients with autism spectrum disorder, but its biological significance remains unclear. In this study, we analyzed the nuclear dynamics of TOP2B with H58Y (TOP2B H58Y). Although wild-type TOP2B was highly mobile in the nucleus of a living cell, the nuclear mobility of TOP2B H58Y was markedly reduced, suggesting that the impact of H58Y manifests as low protein mobility. We found that TOP2B H58Y is insensitive to ICRF-187, a TOP2 inhibitor that halts TOP2 as a closed clamp on DNA. When the ATPase activity of TOP2B was compromised, the nuclear mobility of TOP2B H58Y was restored to wild-type levels, indicating the contribution of the ATPase activity to the low nuclear mobility. Analysis of genome-edited cells harboring TOP2B H58Y showed that TOP2B H58Y retains sensitivity to the TOP2 poison etoposide, implying that TOP2B H58Y can undergo at least a part of its catalytic reactions. Collectively, TOP2 H58Y represents a unique example of the relationship between a disease-associated mutation and perturbed protein dynamics.
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影响因子：
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