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首页> 外文期刊>Molecular and Cellular Biology >Nucleotide Composition of Cellular Internal Ribosome Entry Sites Defines Dependence on NF45 and Predicts a Posttranscriptional Mitotic Regulon
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Nucleotide Composition of Cellular Internal Ribosome Entry Sites Defines Dependence on NF45 and Predicts a Posttranscriptional Mitotic Regulon

机译：细胞内部核糖体进入位点的核苷酸组成定义了对NF45的依赖性，并预测了转录后的有丝分裂调节子。

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The vast majority of cellular mRNAs initiate their translations through a well-defined mechanism of ribosome recruitment that occurs at the 5′-terminal 7-methylguanosine cap with the help of several canonical protein factors. A subset of cellular and viral mRNAs contain regulatory motifs in their 5′ untranslated regions (UTRs), termed internal ribosome entry sites (IRES), that sidestep this canonical mode of initiation. On cellular mRNAs, this mechanism requires IRES trans-acting protein factors (ITAFs) that facilitate ribosome recruitment downstream of the cap. While several ITAFs and their target mRNAs have been empirically identified, the in silico prediction of targets has proved difficult. Here, we report that a high AU content (>60%) of the IRES-containing 5′ UTRs serves as an excellent predictor of dependence on NF45, a recently identified ITAF. Moreover, we provide evidence that cells deficient in NF45 ITAF activity exhibit reduced IRES-mediated translation of X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 (cIAP1) mRNAs that, in turn, leads to dysregulated expression of their respective targets, survivin and cyclin E. This specific defect in IRES translation explains in part the cytokinesis impairment and senescence-like phenotype observed in HeLa cells expressing NF45 RNA interference (RNAi). This study uncovers a novel role for NF45 in regulating ploidy and highlights the importance of IRES-mediated translation in cellular homeostasis.
机译：绝大多数细胞mRNA通过一种确定的核糖体募集机制启动其翻译，该机制在几种典型蛋白质因子的帮助下发生在5'-末端7-甲基鸟苷帽上。细胞和病毒mRNA的子集在其5'非翻译区（UTR）（称为内部核糖体进入位点（IRES））中包含调节基序，从而避免了这种典型的启动方式。在细胞mRNA上，这种机制需要IRES的反式作用蛋白因子（ITAF），以促进帽状核糖体下游的募集。尽管已经凭经验确定了几种ITAF及其靶标mRNA，但事实证明对靶标的计算机预测是困难的。在这里，我们报道了最近发现的ITAF，包含IRES的5'UTR的高AU含量（> 60％）可以很好地预测对NF45的依赖性。此外，我们提供的证据表明，缺乏NF45 ITAF活性的细胞表现出减少的IRES介导的X连锁凋亡蛋白（XIAP）抑制剂和细胞凋亡蛋白1（cIAP1）mRNA抑制剂的翻译，从而导致NF45 ITAF的表达失调。 IRES翻译中的这一特定缺陷部分解释了在表达NF45 RNA干扰（RNAi）的HeLa细胞中观察到的胞质分裂障碍和衰老样表型。这项研究揭示了NF45在调节倍性方面的新作用，并强调了IRES介导的翻译在细胞稳态中的重要性。

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