The long non-coding RNA ROSALIND protects the mitochondrial translational machinery from oxidative damage

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-09-18 DOI:10.1038/s41418-024-01377-4
Vicky Katopodi, Alessandro Marino, Nikoleta Pateraki, Yvessa Verheyden, Sonia Cinque, Elena Lara Jimenez, Sara Adnane, Ewout Demesmaeker, Alice Scomparin, Rita Derua, Elisabetta Groaz, Eleonora Leucci
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Abstract

Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognising and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNA ROSALIND as an interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity both in vitro and ex vivo in preclinical humanised cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

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长非编码 RNA ROSALIND 保护线粒体翻译机制免受氧化损伤
线粒体呼吸的上调与高 ROS 清除能力是几种癌症耐药细胞的共同特征。由于翻译保真度对细胞健康至关重要,因此保护线粒体和细胞质核糖体免受氧化损伤至关重要。通过进行针对线粒体基质的抗坏血酸聚氧乙烯醚酶(APEX)-邻近连接测定,然后分离与线粒体蛋白相关的 RNA 并进行测序,我们确定了核编码的 lncRNA ROSALIND 是核糖体的相互作用伙伴。ROSALIND在复发性肿瘤中上调,它的表达可以区分黑色素瘤患者队列中对免疫检查点阻断有反应和无反应者。ROSALIND 的 G 含量异常高,是一种氧化底物。因此,抑制 ROSALIND 会导致 ROS 和蛋白质氧化增加,造成严重的线粒体呼吸缺陷。这反过来又损害了黑色素瘤细胞的活力,并增加了临床前人源化癌症模型体外和体内的免疫原性。这些发现强调了 ROSALIND 作为一种新型 ROS 缓冲系统的作用,它能保护线粒体翻译免受氧化应激,并揭示了克服癌症治疗耐药性的潜在治疗策略。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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