带有 KRAB 结构域的 pogo 转座元件通过核糖体生物生成限制产生抑癌活性

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-10-30 DOI:10.1016/j.molcel.2024.09.025

Zhenbo Tu, Mahmoud A. Bassal, George W. Bell, Yanzhou Zhang, Yi Hu, Liza M. Quintana, Deeptha Gokul, Daniel G. Tenen, Antoine E. Karnoub

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引用次数: 0

摘要

可转座元件（TE）是人类发育过程中不可或缺的元素，在多能性和胚胎发生过程中发挥着关键作用。可转座元件序列作为顺式/反式转录调控因子、非编码 RNA 的来源以及破坏肿瘤抑制因子的突变因子，对人类病症（尤其是癌症）也有贡献。尽管有这些知识，但人们对 TE 衍生基因（TEG）参与肿瘤发病机制的情况知之甚少。在这里，对人类癌症中 TEG 表达的系统分析揭示了具有 KRAB 结构域的 pogo TE 派生基因（POGK）的重要作用。我们发现，POGK 在三阴性乳腺癌（TNBC）细胞中充当肿瘤抑制因子，它与共抑制因子 TRIM28 相互耦合，直接阻断核糖体基因 RPS16 和 RPS29 的转录，进而导致核糖体生物发生的广泛抑制。我们报告说，在临床 TNBC 中，POGK 通过异构体转换而失活，从而揭示了它在肿瘤生长控制中的特殊活性。

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Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction

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Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction

Transposable elements (TEs) are indispensable for human development, with critical functions in pluripotency and embryogenesis. TE sequences also contribute to human pathologies, especially cancer, with documented activities as cis/trans transcriptional regulators, as sources of non-coding RNAs, and as mutagens that disrupt tumor suppressors. Despite this knowledge, little is known regarding the involvement of TE-derived genes (TEGs) in tumor pathogenesis. Here, systematic analyses of TEG expression across human cancer reveal a prominent role for pogo TE derived with KRAB domain (POGK). We show that POGK acts as a tumor suppressor in triple-negative breast cancer (TNBC) cells and that it couples with the co-repressor TRIM28 to directly block the transcription of ribosomal genes RPS16 and RPS29, in turn causing widespread inhibition of ribosomal biogenesis. We report that POGK undergoes deactivation by isoform switching in clinical TNBC, altogether revealing its exapted activities in tumor growth control.

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.