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Oncogene-dependent sloppiness in mRNA translation
Molecular Cell ( IF 16.0 ) Pub Date : 2021-09-24 , DOI: 10.1016/j.molcel.2021.09.002
Julien Champagne 1 , Abhijeet Pataskar 1 , Naomi Blommaert 1 , Remco Nagel 1 , Demi Wernaart 1 , Sofia Ramalho 1 , Juliana Kenski 2 , Onno B Bleijerveld 3 , Esther A Zaal 4 , Celia R Berkers 4 , Maarten Altelaar 5 , Daniel S Peeper 2 , William J Faller 1 , Reuven Agami 6
Affiliation  

mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown. Here, we show that tryptophan depletion-induced ribosomal frameshifting is a widespread phenomenon in cancer. We termed this event sloppiness and strikingly observed its association with MAPK pathway hyperactivation. Sloppiness is stimulated by RAS activation in primary cells, suppressed by pharmacological inhibition of the oncogenic MAPK pathway in sloppy cells, and restored in cells with acquired resistance to MAPK pathway inhibition. Interestingly, sloppiness causes aberrant peptide presentation at the cell surface, allowing recognition and specific killing of drug-resistant cancer cells by T lymphocytes. Thus, while oncogenes empower cancer progression and aggressiveness, they also expose a vulnerability by provoking the production of aberrant peptides through sloppiness.



中文翻译:

mRNA翻译中的癌基因依赖性马虎

mRNA翻译是蛋白质合成的高度保守和严格控制的机制。尽管有蛋白质质量控​​制机制,但黑色素瘤中的氨基酸短缺会通过核糖体移码诱导异常蛋白质。与这种现象相关的程度和潜在机制尚不清楚。在这里,我们表明色氨酸消耗诱导的核糖体移码是癌症中普遍存在的现象。我们将此事件称为草率,并引人注目地观察到它与 MAPK 通路过度激活的关联。草率通过RAS活化的原代细胞的刺激,通过在稀松细胞致癌MAPK通路的药理学抑制抑制,并且与到MAPK途径抑制的获得性抗性的细胞恢复。有趣的是,马虎导致细胞表面的异常肽呈递,使T淋巴细胞能够识别和特异性杀死耐药癌细胞。因此,虽然癌基因增强了癌症的进展和侵袭性,但它们也通过马虎刺激异常肽的产生而暴露了脆弱性。

更新日期:2021-11-18
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