Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.
Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.
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DOI：
10.1038/s41556-022-00856-5
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发表时间：
2022-03
影响因子：
21.3
通讯作者：
Tavazoie SF
中科院分区：
文献类型：
--
作者：
Passarelli MC;Pinzaru AM;Asgharian H;Liberti MV;Heissel S;Molina H;Goodarzi H;Tavazoie SF
肿瘤发生和癌症进展需要增强的整体蛋白质翻译。这种增强的翻译是由致癌和肿瘤抑制事件引起的，这些事件驱动翻译机制的合成和活性。在这里，我们报告了令人惊讶的观察，亮氨酰-tRNA合成酶（LARS）在乳腺细胞转化和人类乳腺癌中受到抑制。小鼠乳腺LARS单等位基因缺失增强乳腺癌肿瘤形成和增殖。LARS抑制减少了选择亮氨酸tRNA异源受体的丰度，导致包括上皮膜蛋白3（EMP 3）和γ-谷氨酰转移酶5（GGT 5）在内的生长抑制基因的亮氨酸密码子依赖性翻译受损。我们的研究结果揭示了一种肿瘤抑制性tRNA合成酶，并揭示了一种特定tRNA合成酶及其下游同源tRNAs的动态抑制产生了一种下游密码子偏向的翻译基因网络反应，这种反应增强了乳腺肿瘤的形成和生长。
Tumourigenesis and cancer progression require enhanced global protein translation. Such enhanced translation is caused by oncogenic and tumour suppressive events that drive the synthesis and activity of translational machinery. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer. Monoallelic genetic deletion of LARS in mouse mammary glands enhanced breast cancer tumour formation and proliferation. LARS repression reduced the abundance of select leucine tRNA isoacceptors, leading to impaired leucine codon-dependent translation of growth suppressive genes including epithelial membrane protein 3 (EMP3) and gamma-glutamyltransferase 5 (GGT5). Our findings uncover a tumour suppressive tRNA synthetase and reveal that dynamic repression of a specific tRNA synthetase—along with its downstream cognate tRNAs—elicits a downstream codon-biased translational gene network response that enhances breast tumour formation and growth.
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