Decoding mechanisms by which silent codon changes influence protein biogenesis and function.
Decoding mechanisms by which silent codon changes influence protein biogenesis and function.
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DOI：
10.1016/j.biocel.2015.03.011
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发表时间：
2015-07
影响因子：
4
通讯作者：
Bebok, Zsuzsanna
中科院分区：
文献类型：
--
作者：
Bali, Vedrana;Bebok, Zsuzsanna
自遗传密码及其冗余性发现以来，同义密码子的使用一直是研究的焦点。同义密码子的出现在不同物种和同一基因组的基因中是不同的，称为密码子使用偏差。今天，生物信息学和实验数据使我们能够对遗传密码的冗余有助于生物系统复杂性的机制形成一个全局视图，从影响原核生物的生存，到微调高等真核生物蛋白质的结构和功能。研究表明，在不改变氨基酸序列的情况下，同义密码子的改变会影响核酸的稳定性、蛋白质水平、结构和功能。因此，同义突变不可避免地有助于复杂的人类疾病的发病机制。然而，关于沉默突变对人类疾病的影响的基本问题仍未得到解决。在目前的回顾中，我们描述了这一领域的发展，集中在同义突变可能影响蛋白质功能和人类健康的机制。这个概要说明了同义突变在疾病发病机制中的意义。我们回顾了基因表达受沉默突变影响的不同阶段，并评估了密码子优化在治疗性生物制剂开发中的益处和可能的有害影响。了解同义突变导致复杂疾病（如癌症、神经退行性疾病和遗传疾病）的机制，包括密码子优化生物制剂的局限性，为沉默变异的解释和未来的分子治疗提供了见解。
Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies.
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