The effects of structure on pre-mRNA processing and stability.
The effects of structure on pre-mRNA processing and stability.
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DOI：
10.1016/j.ymeth.2017.06.001
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Fairbrother WG
中科院分区：
文献类型：
--
作者：
Soemedi R;Cygan KJ;Rhine CL;Glidden DT;Taggart AJ;Lin CL;Fredericks AM;Fairbrother WG
前体mRNA分子可以形成多种结构，二级和三级结构对这些分子的加工、功能和稳定性具有重要影响。RNA二级结构的预测是一个具有挑战性的问题和各种算法，使用最小的自由能，最大的预期精度和比较进化为基础的方法已被开发来预测二级结构。然而，这些工具并不完美，这仍然是一个活跃的研究领域。前体mRNA分子的二级结构可以对前体mRNA剪接具有增强或抑制作用。增强结构的一个例子可以在斑马鱼的一类新的内含子中找到。大约10%的斑马鱼基因包含一个结构化内含子，该内含子形成一个桥接发夹，可以强制正确的剪接位点配对。剪接的负面例子包括剪接位点周围的局部结构，其降低剪接效率并可能引起导致疾病的错误剪接。剪接突变是遗传性疾病的常见原因。疾病基因的转录本在剪接位点周围的结构明显更好，增加局部结构的点突变通常会导致剪接中断。剪接后，RNA二级结构也可以影响剪接内含子和调节RNA干扰途径中间体（如前体microRNA）的稳定性。此外，RNA二级结构在针对病毒的先天免疫防御中具有重要作用。最后，三级结构也可以在前体mRNA剪接中发挥重要作用。一个例子是G-四链体结构，其类似于二级结构，可以通过诸如产生或遮蔽RNA结合蛋白位点的机制来增强或抑制剪接。
Pre-mRNA molecules can form a variety of structures, and both secondary and tertiary structures have important effects on processing, function and stability of these molecules. The prediction of RNA secondary structure is a challenging problem and various algorithms that use minimum free energy, maximum expected accuracy and comparative evolutionary based methods have been developed to predict secondary structures. However, these tools are not perfect, and this remains an active area of research. The secondary structure of pre-mRNA molecules can have an enhancing or inhibitory effect on pre-mRNA splicing. An example of enhancing structure can be found in a novel class of introns in zebrafish. About 10% of zebrafish genes contain a structured intron that forms a bridging hairpin that enforces correct splice site pairing. Negative examples of splicing include local structures around splice sites that decrease splicing efficiency and potentially cause mis-splicing leading to disease. Splicing mutations are a frequent cause of hereditary disease. The transcripts of disease genes are significantly more structured around the splice sites, and point mutations that increase the local structure often cause splicing disruptions. Post-splicing, RNA secondary structure can also affect the stability of the spliced intron and regulatory RNA interference pathway intermediates, such as pre-microRNAs. Additionally, RNA secondary structure has important roles in the innate immune defense against viruses. Finally, tertiary structure can also play a large role in pre-mRNA splicing. One example is the G-quadruplex structure, which, similar to secondary structure, can either enhance or inhibit splicing through mechanisms such as creating or obscuring RNA binding protein sites.
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