美国哥伦比亚大学吴雪兵研究团队揭示非编码翻译的缓解。这一研究成果于2023年4月12日在线发表在国际学术期刊《自然》上。
研究人员将10000多个人类基因组序列和数百万个随机序列的大规模并行分析与全基因组CRISPR筛选结合起来，并伴随着深入的遗传和生化特征分析。结果显示，非编码基因组和遗传密码中固有的核苷酸偏向经常导致多肽具有疏水性的C端尾巴，它被核糖体相关的BAG6膜蛋白分流复合物捕获，用于蛋白体降解或膜靶向。相比之下，典型的蛋白质已经演化到耗尽C端疏水残基。这些研究结果揭示了对来自不同非编码区的不需要的翻译进行监控的故障安全机制，并提出了新演化蛋白质优先膜定位的潜在生化途径。
据悉，翻译普遍存在于经典编码区之外，发生在长非编码RNA、经典非翻译区和内含子，特别是在衰老、神经变性和癌症中。值得注意的是，大多数肿瘤特异性抗原都是非编码翻译的结果。虽然所产生的多肽往往是无功能的，但非编码区的翻译对新的编码序列的诞生是必要的。对不同非编码区翻译的监控机制以及逃逸的多肽如何进化出新的功能仍不清楚。从有注释的非编码序列衍生出的功能多肽经常定位到膜上。
附：英文原文
Title: Noncoding translation mitigation
Author: Kesner, Jordan S., Chen, Ziheng, Shi, Peiguo, Aparicio, Alexis O., Murphy, Michael R., Guo, Yang, Trehan, Aditi, Lipponen, Jessica E., Recinos, Yocelyn, Myeku, Natura, Wu, Xuebing
Issue&Volume: 2023-04-12
Abstract: Translation is pervasive outside of canonical coding regions, occurring in long noncoding RNAs, canonical untranslated regions and introns1,2,3,4, especially in ageing4,5,6, neurodegeneration5,7 and cancer8,9,10. Notably, the majority of tumour-specific antigens are results of noncoding translation11,12,13. Although the resulting polypeptides are often nonfunctional, translation of noncoding regions is nonetheless necessary for the birth of new coding sequences14,15. The mechanisms underlying the surveillance of translation in diverse noncoding regions and how escaped polypeptides evolve new functions remain unclear10,16,17,18,19. Functional polypeptides derived from annotated noncoding sequences often localize to membranes20,21. Here we integrate massively parallel analyses of more than 10,000 human genomic sequences and millions of random sequences with genome-wide CRISPR screens, accompanied by in-depth genetic and biochemical characterizations. Our results show that the intrinsic nucleotide bias in the noncoding genome and in the genetic code frequently results in polypeptides with a hydrophobic C-terminal tail, which is captured by the ribosome-associated BAG6 membrane protein triage complex for either proteasomal degradation or membrane targeting. By contrast, canonical proteins have evolved to deplete C-terminal hydrophobic residues. Our results reveal a fail-safe mechanism for the surveillance of unwanted translation from diverse noncoding regions and suggest a possible biochemical route for the preferential membrane localization of newly evolved proteins.
DOI: 10.1038/s41586-023-05946-4
Source: https://www.nature.com/articles/s41586-023-05946-4
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
