Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis.

IF 23.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2024-10-22 DOI:10.1038/s43018-024-00844-8

Leona A Nease, Kellsey P Church, Ines Delclaux, Shino Murakami, Maider Astorkia, Marwa Zerhouni, Graciela Cascio, Riley O Hughes, Kelsey N Aguirre, Paul Zumbo, Lukas E Dow, Samie Jaffrey, Doron Betel, Elena Piskounova

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引用次数: 0

Abstract

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNA^Sec isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNA^Sec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.

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硒半胱氨酸 tRNA 甲基化促进黑色素瘤转移过程中的氧化应激抵抗力

含硒半胱氨酸的蛋白质在氧化还原平衡中发挥着核心作用。它们的翻译是一个高度受调控的过程，依赖于两个 tRNASec 同编码器，这两个同编码器之间存在一个称为 Um34 的 2'-O-ribose 甲基化。在这里，我们将 FTSJ1 鉴定为 Um34 甲基转移酶，并证明其活性是翻译过程中在 UGA 终止密码子处有效插入硒半胱氨酸所必需的。具体来说，Um34 的缺失会导致核糖体停滞和 UGA 重编码的减少。FTSJ1缺陷细胞对氧化应激更敏感，并在黑色素瘤转移的异种移植模型中显示出转移定植能力下降。我们发现，FTSJ1介导了对细胞抗氧化反应至关重要的硒蛋白的高效翻译。我们的研究结果揭示了 tRNASec Um34 修饰在氧化应激抵抗中的作用，并强调 FTSJ1 是转移性疾病的一个潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.