The RAS GTPase RIT1 compromises mitotic fidelity through spindle assembly checkpoint suppression.
The RAS GTPase RIT1 compromises mitotic fidelity through spindle assembly checkpoint suppression.
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DOI：
10.1016/j.cub.2021.06.030
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发表时间：
2021-09-13
期刊：
影响因子：
--
通讯作者：
McCormick F
中科院分区：
文献类型：
--
作者：
Cuevas-Navarro A;Van R;Cheng A;Urisman A;Castel P;McCormick F
纺锤体组装检查点（SAC）的功能是作为一个传感器的未连接的着丝粒，延迟有丝分裂进入后期，直到正确的染色体分离得到保证。这种安全机制的破坏导致基因组不稳定和非整倍体，这是胚胎死亡、先天性出生缺陷、智力残疾和癌症的遗传原因。然而，尽管了解控制SAC的基本机制，但仍然不知道信号通路如何直接与有丝分裂检查点活性相互作用并调节有丝分裂检查点活性。响应于细胞外刺激，参与细胞生长、存活和分化的多种信号传导途径网络被激活，并且该过程主要由小鸟苷三磷酸酶（GTP酶）的Ras家族调节。在这里，我们表明，RIT 1，一个Ras相关的GTdR，调节细胞存活和应激反应，是通过有丝分裂和适当的染色体分离及时进展所必需的。RIT 1在有丝分裂期间从质膜（PM）上解离，并在受细胞周期蛋白依赖性激酶1（CDK 1）活性调节的过程中直接与SAC蛋白MAD 2和p31彗星相互作用。此外，致病水平的RIT 1沉默SAC，并通过从有丝分裂检查点复合物（MCC）中隔离MAD 2来加速通过有丝分裂的转运。此外，致病性RIT 1对SAC的抑制促进了染色体分离错误和非整倍体。我们的研究结果突出了RIT 1的独特功能相比，其他Ras GTP酶和阐明信号通路和SAC之间的直接联系，通过一种新的监管机制。Cuevas-Navarro等人描述了Ras GTCRIT 1的一种新功能，通过与MAD 2和p31彗星的直接相互作用，作为纺锤体组装检查点（SAC）的负调节因子。此外，逃避蛋白质周转的疾病相关RIT 1突变促进染色体分离错误和非整倍性。
The spindle assembly checkpoint (SAC) functions as a sensor of unattached kinetochores that delays mitotic progression into anaphase until proper chromosome segregation is guaranteed. Disruptions to this safety mechanism lead to genomic instability and aneuploidy, which serve as the genetic cause of embryonic demise, congenital birth defects, intellectual disability, and cancer. However, despite the understanding of the fundamental mechanisms that control the SAC, it remains unknown how signaling pathways directly interact with and regulate the mitotic checkpoint activity. In response to extracellular stimuli, a diverse network of signaling pathways involved in cell growth, survival, and differentiation are activated and this process is prominently regulated by the Ras family of small guanosine triphosphatases (GTPases). Here we show that RIT1, a Ras-related GTPase that regulates cell survival and stress response, is essential for timely progression through mitosis and proper chromosome segregation. RIT1 dissociates from the plasma membrane (PM) during mitosis and interacts directly with SAC proteins MAD2 and p31comet in a process that is regulated by cyclin-dependent kinase 1 (CDK1) activity. Furthermore, pathogenic levels of RIT1 silence the SAC and accelerate transit through mitosis by sequestering MAD2 from the mitotic checkpoint complex (MCC). Moreover, SAC suppression by pathogenic RIT1 promotes chromosome segregation errors and aneuploidy. Our results highlight a unique function of RIT1 compared to other Ras GTPases and elucidate a direct link between a signaling pathway and the SAC through a novel regulatory mechanism. Cuevas-Navarro et al. characterize a novel function of the Ras GTPase RIT1 as a negative regulator of the spindle assembly checkpoint (SAC) through its direct interaction with MAD2 and p31comet. Moreover, disease-associated RIT1 mutations that evade protein turnover promote chomosome segregation errors and aneuploidy.
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