Oncogenomics Unit, Core Research Laboratory, ISPRO, Pisa, Italy.
Institute of Clinical Physiology, CNR, Pisa, Italy.
Cell Res. 2024 Sep;34(9):609-629. doi: 10.1038/s41422-024-00975-8. Epub 2024 Jul 25.
The advent of high-throughput sequencing uncovered that our genome is pervasively transcribed into RNAs that are seemingly not translated into proteins. It was also found that non-coding RNA transcripts outnumber canonical protein-coding genes. This mindboggling discovery prompted a surge in non-coding RNA research that started unraveling the functional relevance of these new genetic units, shaking the classic definition of "gene". While the non-coding RNA revolution was still taking place, polysome/ribosome profiling and mass spectrometry analyses revealed that peptides can be translated from non-canonical open reading frames. Therefore, it is becoming evident that the coding vs non-coding dichotomy is way blurrier than anticipated. In this review, we focus on several examples in which the binary classification of coding vs non-coding genes is outdated, since the same bifunctional gene expresses both coding and non-coding products. We discuss the implications of this intricate usage of transcripts in terms of molecular mechanisms of gene expression and biological outputs, which are often concordant, but can also surprisingly be discordant. Finally, we discuss the methodological caveats that are associated with the study of bifunctional genes, and we highlight the opportunities and challenges of therapeutic exploitation of this intricacy towards the development of anticancer therapies.
高通量测序的出现揭示了我们的基因组广泛转录成 RNA，而这些 RNA 似乎没有被翻译成蛋白质。此外，人们还发现非编码 RNA 转录本的数量超过了典型的编码蛋白质的基因。这一令人惊讶的发现促使非编码 RNA 研究的激增，该研究开始揭示这些新的遗传单位的功能相关性，动摇了“基因”的经典定义。在非编码 RNA 革命仍在进行之际，多核糖体/核糖体分析和质谱分析表明，非典型开放阅读框可以翻译出肽。因此，编码与非编码的二分法比预期的要模糊得多，这一点变得越来越明显。在这篇综述中，我们重点介绍了几个例子，其中编码与非编码基因的二元分类已经过时，因为同一个双功能基因既表达编码产物又表达非编码产物。我们讨论了这种复杂的转录本在基因表达和生物学产物的分子机制方面的影响，这些影响通常是一致的，但也可能令人惊讶地不一致。最后，我们讨论了研究双功能基因时存在的方法学上的局限性，并强调了利用这种复杂性开发抗癌疗法的机会和挑战。
