Genotoxic stress triggers Scd6-dependent regulation of translation to modulate the DNA damage response.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-05-01 Epub Date: 2025-04-24 DOI:10.1038/s44319-025-00443-3

Gayatri Mohanan, Raju Roy, Hélène Malka-Mahieu, Swati Lamba, Lucilla Fabbri, Sidhant Kalia, Anusmita Biswas, Sylvain Martineau, Céline M Labbé, Stéphan Vagner, Purusharth I Rajyaguru

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引用次数: 0

Abstract

The role of mRNA translation and decay in the genotoxic stress response remains poorly explored. Here, we identify the role of yeast RGG motif-containing RNA binding protein Scd6 and its human ortholog LSM14A in genotoxic stress response. Scd6 localizes to cytoplasmic puncta upon cell treatment with various genotoxic agents. Scd6 genetically interacts with SRS2, a DNA helicase with an anti-recombination role in DNA damage repair under HU stress. Scd6 directly interacts with the SRS2 mRNA to repress its translation in cytoplasmic granules upon HU stress in an eIF4G1-independent manner. Scd6-SRS2 interaction is modulated by arginine methylation and the LSm-domain of Scd6, which acts as a cis-regulator of Scd6 arginine methylation. LSM14A regulates the translation of mRNAs encoding key NHEJ (Non-homologous end-joining) proteins such as RTEL1 (SRS2 functional homolog) and LIG4. NHEJ activity in yeast and mammalian cells is regulated by Scd6 and LSM14A, respectively. Overall, this report unveils the role of RNA binding proteins in regulating the translation of specific mRNAs coding for DNA damage response proteins upon genotoxic stress.

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基因毒性应激触发依赖于scd6的翻译调控来调节DNA损伤反应。

mRNA的翻译和衰变在基因毒性应激反应中的作用仍未得到充分探讨。在此，我们确定了酵母RGG基序RNA结合蛋白Scd6及其人类同源物LSM14A在基因毒性应激反应中的作用。Scd6在各种基因毒性药物的作用下定位于细胞质点。Scd6基因与SRS2相互作用，SRS2是一种DNA解旋酶，在HU胁迫下的DNA损伤修复中具有抗重组作用。在HU胁迫下，Scd6直接与SRS2 mRNA相互作用，以不依赖eif4g1的方式抑制SRS2 mRNA在细胞质颗粒中的翻译。Scd6- srs2相互作用受精氨酸甲基化和Scd6的lsm结构域调节，lsm结构域作为Scd6精氨酸甲基化的顺式调节因子。LSM14A调控编码关键NHEJ（非同源末端连接）蛋白的mrna的翻译，如RTEL1 （SRS2功能同源）和LIG4。酵母和哺乳动物细胞中的NHEJ活性分别受Scd6和LSM14A的调控。总的来说，本报告揭示了RNA结合蛋白在基因毒性胁迫下调节编码DNA损伤反应蛋白的特定mrna翻译中的作用。

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

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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