文章：

无义介导的RNA衰变：一种新兴的恶性肿瘤调节剂

Nonsense-mediated RNA decay: an emerging modulator of malignancy

原文发布日期：2022-05-27

DOI: 10.1038/s41568-022-00481-2

类型: Review Article

开放获取: 否

英文摘要：

Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.

摘要翻译： 

无义介导的RNA降解（NMD）是一种高度保守的RNA周转途径，选择性降解携带导致翻译提前终止的截短突变的RNA，包括无义突变、移码突变和某些剪接位点突变。近期研究表明，NMD通过筛选倾向于下调抑癌基因表达但不影响癌基因的突变，塑造了肿瘤的突变谱。这提示NMD可能对肿瘤有利，这一观点也得到进一步支持：编码免疫原性新抗原肽的mRNA通常是NMD的降解靶标。综上，这提出了NMD抑制疗法可能对多种肿瘤类型（包括新抗原突变负荷高的肿瘤）具有治疗益处的可能性。然而，情况更为复杂的是，有证据表明NMD对许多肿瘤类型也可能有害，因此肿瘤常存在NMD功能紊乱。NMD可通过降解特定正常mRNA亚群（包括编码应激反应蛋白、信号因子及其他对肿瘤有益的蛋白的mRNA）以及促肿瘤非编码RNA，抑制肿瘤的发生与进展。综上，这些发现提示NMD调节疗法可能对多种肿瘤类型具有广泛的治疗潜力。但是，究竟应激活还是抑制NMD，需对拟治疗的肿瘤进行仔细分析。

原文链接：

Nonsense-mediated RNA decay: an emerging modulator of malignancy