Loughran Gary, Andreev Dmitry E, Terenin Ilya M, Namy Olivier, Mikl Martin, Yordanova Martina M, McManus C Joel, Firth Andrew E, Atkins John F, Fraser Christopher S, Ignatova Zoya, Iwasaki Shintaro, Kufel Joanna, Larsson Ola, Leidel Sebastian A, Mankin Alexander S, Mariotti Marco, Tanenbaum Marvin E, Topisirovic Ivan, Vázquez-Laslop Nora, Viero Gabriela, Caliskan Neva, Chen Yiwen, Clark Patricia L, Dinman Jonathan D, Farabaugh Philip J, Gilbert Wendy V, Ivanov Pavel, Kieft Jeffrey S, Mühlemann Oliver, Sachs Matthew S, Shatsky Ivan N, Sonenberg Nahum, Steckelberg Anna-Lena, Willis Anne E, Woodside Michael T, Valasek Leos Shivaya, Dmitriev Sergey E, Baranov Pavel V
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
EIRNA Bio, Bioinnovation Hub, Cork, Ireland.
Nat Struct Mol Biol. 2025 Mar;32(3):418-430. doi: 10.1038/s41594-025-01492-x. Epub 2025 Mar 3.
Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. These effects may occur due to cryptic regulatory elements inducing or affecting transcription initiation, splicing, polyadenylation and antisense transcription as well as unpredictable effects of the translated test sequences on the stability and activity of the reporters. Unfortunately, these unintended effects may lead to misinterpretation of data and the publication of incorrect conclusions in the scientific literature. To address this issue and to assist the scientific community in accurately interpreting dual-reporter experiments, we have developed comprehensive guidelines. These guidelines cover experimental design, interpretation and the minimal requirements for reporting results. They are designed to aid researchers conducting these experiments as well as reviewers, editors and other investigators who seek to evaluate published data.
在同一信使核糖核酸(mRNA)中编码两种不同蛋白质的双报告基因,在识别和表征真核生物翻译的非常规机制方面发挥了关键作用。这些机制包括通过内部核糖体进入位点(IRES)起始翻译、核糖体移码、终止密码子通读和重新起始。这种设计使得一个报告基因的表达受到所研究的特定机制的影响,而另一个报告基因则作为内部对照。然而,当在这两个报告基因之间插入干预测试序列时,就会出现问题。这些序列可能会在与翻译相关的变化之外,无意中影响任一报告基因的表达或功能,从而可能使结果产生偏差。这些影响可能是由于隐蔽的调控元件诱导或影响转录起始、剪接、聚腺苷酸化和反义转录,以及翻译后的测试序列对报告基因的稳定性和活性产生不可预测的影响。不幸的是,这些意外影响可能导致对数据的错误解读,并在科学文献中发表错误结论。为了解决这个问题,并帮助科学界准确解释双报告基因实验,我们制定了全面的指南。这些指南涵盖实验设计、解释以及报告结果的最低要求。它们旨在帮助进行这些实验的研究人员以及寻求评估已发表数据的审稿人、编辑和其他研究人员。