TRF1 Ensures the Centromeric Function of Aurora-B and Proper Chromosome Segregation
TRF1 Ensures the Centromeric Function of Aurora-B and Proper Chromosome Segregation
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DOI：
10.1128/mcb.00161-14
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发表时间：
2014-07-01
影响因子：
5.3
通讯作者：
Seimiya, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ohishi, Tomokazu;Muramatsu, Yukiko;Seimiya, Hiroyuki
癌症是源自正常二倍体细胞的不断进化的细胞群。不正确的染色体分离会导致非整倍性，这是癌症发生和恶性进展的驱动力。端粒重复结合因子 1 (TRF1) 已被确定为一种端粒蛋白，可通过端粒酶负向调节端粒伸长并促进端粒处的有效 DNA 复制。有趣的是，有丝分裂激酶 Aurora-A 的过度表达会以 TRF1 依赖性方式损害有效的微管-动粒附着。然而，TRF1 在有丝分裂中的确切作用仍然难以捉摸。在这里，我们证明 TRF1 是 Aurora-B 着丝粒功能所必需的，这确保了正确的染色体分离。 TRF1 耗竭消除了 Aurora-B 着丝粒的募集并放松了姐妹着丝粒的内聚力，从而诱导了裂粒着丝粒附着、滞后染色体和微核。因此，人类和小鼠二倍体细胞中 TRF1 的缺失会诱导非整倍性。这些现象似乎与端粒无关，因为未结合端粒的 TRF1 突变体可以抑制 TRF1 敲低表型。这些观察结果表明，TRF1 调节微管着丝粒附着的刚性，有助于正确的染色体分离和维持基因组完整性。
A cancer is a robustly evolving cell population originating from a normal diploid cell. Improper chromosome segregation causes aneuploidy, a driving force of cancer development and malignant progression. Telomeric repeat binding factor 1 (TRF1) has been established as a telomeric protein that negatively regulates telomere elongation by telomerase and promotes efficient DNA replication at telomeres. Intriguingly, overexpression of a mitotic kinase, Aurora-A, compromises efficient microtubule-kinetochore attachment in a TRF1-dependent manner. However, the precise role of TRF1 in mitosis remains elusive. Here we demonstrate that TRF1 is required for the centromeric function of Aurora-B, which ensures proper chromosome segregation. TRF1 depletion abolishes centromeric recruitment of Aurora-B and loosens sister centromere cohesion, resulting in the induction of merotelic kinetochore attachments, lagging chromosomes, and micronuclei. Accordingly, an absence of TRF1 in human and mouse diploid cells induces aneuploidy. These phenomena seem to be telomere independent, because a telomere-unbound TRF1 mutant can suppress the TRF1 knockdown phenotype. These observations indicate that TRF1 regulates the rigidity of the microtubule- kinetochore attachment, contributing to proper chromosome segregation and the maintenance of genomic integrity.