Kozak Marilyn
Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Gene. 2002 Oct 16;299(1-2):1-34. doi: 10.1016/s0378-1119(02)01056-9.
Selection of the translational initiation site in most eukaryotic mRNAs appears to occur via a scanning mechanism which predicts that proximity to the 5' end plays a dominant role in identifying the start codon. This "position effect" is seen in cases where a mutation creates an AUG codon upstream from the normal start site and translation shifts to the upstream site. The position effect is evident also in cases where a silent internal AUG codon is activated upon being relocated closer to the 5' end. Two mechanisms for escaping the first-AUG rule--reinitiation and context-dependent leaky scanning--enable downstream AUG codons to be accessed in some mRNAs. Although these mechanisms are not new, many new examples of their use have emerged. Via these escape pathways, the scanning mechanism operates even in extreme cases, such as a plant virus mRNA in which translation initiates from three start sites over a distance of 900 nt. This depends on careful structural arrangements, however, which are rarely present in cellular mRNAs. Understanding the rules for initiation of translation enables understanding of human diseases in which the expression of a critical gene is reduced by mutations that add upstream AUG codons or change the context around the AUG(START) codon. The opposite problem occurs in the case of hereditary thrombocythemia: translational efficiency is increased by mutations that remove or restructure a small upstream open reading frame in thrombopoietin mRNA, and the resulting overproduction of the cytokine causes the disease. This and other examples support the idea that 5' leader sequences are sometimes structured deliberately in a way that constrains scanning in order to prevent harmful overproduction of potent regulatory proteins. The accumulated evidence reveals how the scanning mechanism dictates the pattern of transcription--forcing production of monocistronic mRNAs--and the pattern of translation of eukaryotic cellular and viral genes.
大多数真核生物mRNA的翻译起始位点选择似乎是通过一种扫描机制进行的，该机制预测靠近5'端在识别起始密码子中起主导作用。这种“位置效应”在以下情况中可见：突变在正常起始位点上游产生一个AUG密码子，翻译转移到上游位点。在沉默的内部AUG密码子移至更靠近5'端时被激活的情况下，位置效应也很明显。两种逃避首个AUG规则的机制——重新起始和上下文依赖的漏扫描——使一些mRNA中的下游AUG密码子能够被识别。尽管这些机制并不新鲜，但它们的新应用实例不断涌现。通过这些逃避途径，扫描机制甚至在极端情况下也能起作用，比如一种植物病毒mRNA，其翻译从900个核苷酸距离内的三个起始位点开始。然而，这依赖于精细的结构安排，而细胞mRNA中很少存在这种安排。理解翻译起始规则有助于理解人类疾病，在这些疾病中，关键基因的表达因添加上游AUG密码子或改变AUG（起始）密码子周围上下文的突变而降低。相反的问题出现在遗传性血小板增多症中：血小板生成素mRNA中去除或重组一个小的上游开放阅读框的突变会提高翻译效率，细胞因子的过度产生导致了这种疾病。这个例子以及其他例子支持了这样一种观点，即5'前导序列有时会特意构建成一种限制扫描的结构，以防止强效调节蛋白的有害过量产生。积累的证据揭示了扫描机制如何决定转录模式——促使单顺反子mRNA的产生——以及真核细胞和病毒基因的翻译模式。
