无义介导的RNA衰变：恶性肿瘤的一种新兴调节

SCI

12 June 2022

Nonsense-mediated RNA decay: an emerging modulator of malignancy

(Nat Rev Cancer; IF:60.716)

• CORRESPONDENCE TO: dstupack@health.ucsd.edu; mfwilkinson@health.ucsd.edu 

• Tan K, Stupack DG, Wilkinson MF. Nonsense-mediated RNA decay: an emerging modulator of malignancy. Nat Rev Cancer 2022. DOI: 10.1038/s41568-022-00481-2

Abstract | 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.

无意义介导的RNA衰变(nonsense -mediated RNA decay, NMD)是一种高度保守的RNA转换途径，它选择性地降解含有截断突变的RNA，包括无义突变、移码突变和一些剪接位点突变，这些突变会提前终止翻译。最近的研究表明，NMD通过选择倾向于下调肿瘤抑制基因(而非致癌基因)表达的突变，塑造了肿瘤的突变格局。这表明NMD可以使肿瘤受益，编码免疫原性新抗原肽的mRNA通常是NMD衰减的目标，这一发现进一步支持了这一观点。总之，这增加了一种可能性，即NMD抑制疗法可能对许多类型的肿瘤有治疗益处，包括那些具有高负荷新抗原产生突变的肿瘤。使这种情况更加复杂的是，有证据表明NMD也可能对许多肿瘤类型有害，因此肿瘤经常干扰NMD。NMD可能通过降解特定的正常mrna亚群来抑制肿瘤的增殖和进展，包括编码应激反应蛋白、信号因子和其他对肿瘤有益的蛋白，以及促肿瘤的非编码RNA。总之，这些发现表明，NMD调节疗法有可能对不同类型的肿瘤提供广泛的治疗效益。然而，NMD是否应该被刺激或抑制，需要仔细分析要治疗的肿瘤。