SUV39H1 orchestrates temporal dynamics of centromeric methylation essential for faithful chromosome segregation in mitosis
SUV39H1 orchestrates temporal dynamics of centromeric methylation essential for faithful chromosome segregation in mitosis
复制标题
SUV39H1协调着丝粒甲基化的时间动态，这对于有丝分裂中染色体的忠实分离至关重要
DOI：
10.1093/jmcb/mjs023
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发表时间：
2012-10-01
影响因子：
5.5
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Chu, Lingluo;Zhu, Tongge;Yao, Xuebiao
组蛋白甲基化执行多种功能，例如 DNA 复制、转录调节、异染色质形成和染色质浓缩。在染色体分离过程中，这种甲基化梯度如何在着丝粒中协调尚不清楚。在这里，我们使用活 HeLa 细胞中基于荧光共振能量转移的传感器和天然 SUV39H1 底物的免疫荧光，检查 SUV39H1 甲基转移酶（一种关键的有丝分裂调节剂）在着丝粒中蛋白质甲基化的时间动态。使用着丝粒靶向传感器对甲基化动力学进行定量分析，揭示了染色体分离过程中的时间变化。使用 SUV39H1 抑制剂抑制甲基化动态，扰乱活 HeLa 细胞中的染色体会聚，从而导致染色体在赤道上准确地会聚和对齐。令人惊讶的是，这种甲基化抑制导致 Aurora B 激酶活性短暂增加，着丝粒中微管解聚酶 MCAK 富集，同时伴随动粒微管不稳定和姐妹动粒张力降低，最终导致染色体错位。我们推断 SUV39H1 在着丝粒处产生甲基化标记梯度，提供有丝分裂中准确染色体分离所必需的时空信息。
Histone methylation performs multiple functions such as DNA replication, transcription regulation, heterochromatin formation, and chromatin condensation. How this methylation gradient is orchestrated in the centromere during chromosome segregation is not known. Here we examine the temporal dynamics of protein methylation in the centromere by SUV39H1 methyltransferase, a key mitotic regulator, using fluorescence resonance energy transfer-based sensors in living HeLa cells and immunofluorescence of native SUV39H1 substrates. A quantitative analysis of methylation dynamics, using centromere-targeted sensors, reveals a temporal change during chromosome segregation. These dynamics result in an accurate chromosome congression to and alignment at the equator as an inhibition of methylation dynamics using SUV39H1 inhibitor perturbs chromosome congression in living HeLa cells. Surprisingly, this inhibition of methylation results in a brief increase in Aurora B kinase activity and an enrichment of microtubule depolymerase MCAK in the centromere with a concomitant kinetochoremicrotubule destabilization and a reduced tension across the sister kinetochores with ultimate chromosome misalignments. We reason that SUV39H1 generates a gradient of methylation marks at the kinetochore that provides spatiotemporal information essential for accurate chromosome segregation in mitosis.