The Impact of Coilin Nonsynonymous SNP Variants E121K and V145I on Cell Growth and Cajal Body Formation: The First Characterization
The Impact of Coilin Nonsynonymous SNP Variants E121K and V145I on Cell Growth and Cajal Body Formation: The First Characterization
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Coilin 非同义 SNP 变体 E121K 和 V145I 对细胞生长和 Cajal 体形成的影响：首次表征
DOI：
10.3390/genes11080895
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发表时间：
2020-08-01
期刊：
影响因子：
3.5
通讯作者：
Lau，Andy T. Y.
中科院分区：
文献类型：
--
作者：
Yao，Yue;Tan，Heng Wee;Lau，Andy T. Y.
卷曲蛋白是Cajal小体（CB）的主要成分，CB是一种无膜细胞器，参与核糖核蛋白和端粒酶的生物合成、细胞周期和细胞生长。CB的破坏与神经退行性疾病和潜在的癌症有关。coilin基因（COIL）包含两个非同义SNP：rs 116022828（E121 K）和rs61731978（V145 I）。在这里，我们首次研究了这些卷曲蛋白SNP对CB形成、卷曲蛋白亚细胞定位、微管形成、细胞生长以及卷曲蛋白表达和蛋白结构的功能影响。我们发现，E121 K和V145 I突变体可以破坏CB的形成，并导致各种模式的亚细胞定位与生存运动神经元蛋白。值得注意的是，许多E121 K细胞显示核仁卷曲蛋白积聚。微管再生和细胞周期分析表明，E121 K细胞似乎被困在细胞周期的S和G2/M期，导致细胞增殖减少。在计算机蛋白质结构预测表明，E121 K突变引起更大的不稳定性的卷曲蛋白结构比V145 I突变。此外，临床生物信息学分析表明，卷曲蛋白表达水平可能是癌症的风险因素，这取决于癌症类型和种族。
Coilin is the main component of Cajal body (CB), a membraneless organelle that is involved in the biogenesis of ribonucleoproteins and telomerase, cell cycle, and cell growth. The disruption of CBs is linked to neurodegenerative diseases and potentially cancers. The coilin gene (COIL) contains two nonsynonymous SNPs: rs116022828 (E121K) and rs61731978 (V145I). Here, we investigated for the first time the functional impacts of these coilin SNPs on CB formation, coilin subcellular localization, microtubule formation, cell growth, and coilin expression and protein structure. We revealed that both E121K and V145I mutants could disrupt CB formation and result in various patterns of subcellular localization with survival motor neuron protein. Noteworthy, many of the E121K cells showed nucleolar coilin accumulation. The microtubule regrowth and cell cycle assays indicated that the E121K cells appeared to be trapped in the S and G2/M phases of cell cycle, resulting in reduced cell proliferation. In silico protein structure prediction suggested that the E121K mutation caused greater destabilization on the coilin structure than the V145I mutation. Additionally, clinical bioinformatic analysis indicated that coilin expression levels could be a risk factor for cancer, depending on the cancer types and races.