Alternative mechanisms of translation initiation: An emerging dynamic regulator of the proteome in health and disease.
Alternative mechanisms of translation initiation: An emerging dynamic regulator of the proteome in health and disease.
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DOI：
10.1016/j.lfs.2018.09.054
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发表时间：
2018-11-01
期刊：
影响因子：
6.1
通讯作者：
Smyth JW
中科院分区：
文献类型：
--
作者：
James CC;Smyth JW
历史上认为真核mrna完全依赖于起始因子对其5 '帽的识别和结合来影响蛋白质翻译。虽然内部核糖体进入位点（IRESs）被广泛认为是许多病毒基因组的帽无关翻译所必需的，但现在人们认识到真核mrna也经历了非规范的翻译起始模式。最近，高通量分析已经鉴定出数千种翻译起始发生在非规范起始密码子、蛋白质编码区上游和内部的哺乳动物转录本。除了ires介导的事件外，翻译起始的调控机制还涉及5 '帽识别、mRNA序列元件和核糖体选择。这些机制确保了在帽依赖翻译关闭的条件下特定mrna的翻译，并导致包括心脏肥大和癌症在内的病理状态。这种全球性和基因特异性的翻译动态调控为我们提供了越来越多的新的治疗靶点。虽然这些新发现的翻译启动模式在很大程度上是单独研究的，但很可能有几种模式作用于相同的mRNA，并且需要精细的协调才能维持正常的翻译。在这篇简短的综述中，我们总结了真核蛋白翻译的这些替代机制的知识现状，它们对正常和病理细胞生物学的贡献，以及靶向翻译起始治疗人类疾病的潜力。
Eukaryotic mRNAs were historically thought to rely exclusively on recognition and binding of their 5’ cap by initiation factors to effect protein translation. While internal ribosome entry sites (IRESs) are well accepted as necessary for the cap-independent translation of many viral genomes, there is now recognition that eukaryotic mRNAs also undergo non-canonical modes of translation initiation. Recently, high-throughput assays have identified thousands of mammalian transcripts with translation initiation occurring at non-canonical start codons, upstream of and within protein coding regions. In addition to IRES-mediated events, regulatory mechanisms of translation initiation have been described involving alternate 5’ cap recognition, mRNA sequence elements, and ribosome selection. These mechanisms ensure translation of specific mRNAs under conditions where cap-dependent translation is shut down and contribute to pathological states including cardiac hypertrophy and cancer. Such global and gene-specific dynamic regulation of translation presents us with an increasing number of novel therapeutic targets. While these newly discovered modes of translation initiation have been largely studied in isolation, it is likely that several act on the same mRNA and exquisite coordination is necessary to maintain ‘normal’ translation. In this short review, we summarize the current state of knowledge of these alternative mechanisms of eukaryotic protein translation, their contribution to normal and pathological cell biology, and the potential of targeting translation initiation therapeutically in human disease.
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DOI：
10.1073/pnas.0710650105
发表时间：
2008-03-25
影响因子：
11.1
作者：
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影响因子：
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