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鉴定调控由FMR1 5'前导序列介导的翻译内部起始的内在和外在决定因素。

Identifying intrinsic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5' leader.

作者信息

Dobson Tara, Kube Erika, Timmerman Stephanie, Krushel Les A

机构信息

Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.

出版信息

BMC Mol Biol. 2008 Oct 15;9:89. doi: 10.1186/1471-2199-9-89.

DOI:10.1186/1471-2199-9-89
PMID:18922172
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2576346/
Abstract

BACKGROUND

Regulating synthesis of the Fragile X gene (FMR1) product, FMRP alters neural plasticity potentially through its role in the microRNA pathway. Cap-dependent translation of the FMR1 mRNA, a process requiring ribosomal scanning through the 5' leader, is likely impeded by the extensive secondary structure generated by the high guanosine/cytosine nucleotide content including the CGG triplet nucleotide repeats in the 5' leader. An alternative mechanism to initiate translation - internal initiation often utilizes secondary structure to recruit the translational machinery. Consequently, studies were undertaken to confirm and extend a previous observation that the FMR1 5' leader contains an internal ribosomal entry site (IRES).

RESULTS

Cellular transfection of a dicistronic DNA construct containing the FMR1 5' leader inserted into the intercistronic region yielded significant translation of the second cistron, but the FMR1 5' leader was also found to contain a cryptic promoter possibly confounding interpretation of these results. However, transfection of dicistronic and monocistronic RNA ex vivo or in vitro confirmed that the FMR1 5' leader contains an IRES. Moreover, inhibiting cap-dependent translation ex vivo did not affect the expression level of endogenous FMRP indicating a role for IRES-dependent translation of FMR1 mRNA. Analysis of the FMR1 5' leader revealed that the CGG repeats and the 5' end of the leader were vital for internal initiation. Functionally, exposure to potassium chloride or intracellular acidification and addition of polyinosinic:polycytidylic acid as mimics of neural activity and double stranded RNA, respectively, differentially affected FMR1 IRES activity.

CONCLUSION

Our results indicate that multiple stimuli influence IRES-dependent translation of the FMR1 mRNA and suggest a functional role for the CGG nucleotide repeats.

摘要

背景

脆性X基因（FMR1）产物FMRP的合成调控可能通过其在微小RNA途径中的作用改变神经可塑性。FMR1 mRNA的帽依赖性翻译是一个需要核糖体扫描5'前导序列的过程，很可能受到5'前导序列中高鸟嘌呤/胞嘧啶核苷酸含量（包括CGG三核苷酸重复序列）所产生的广泛二级结构的阻碍。一种启动翻译的替代机制——内部起始通常利用二级结构来招募翻译机制。因此，开展了研究以证实并扩展先前的一项观察结果，即FMR1的5'前导序列包含一个内部核糖体进入位点（IRES）。

结果

将含有插入到双顺反子区域间的FMR1 5'前导序列的双顺反子DNA构建体进行细胞转染，产生了第二个顺反子的显著翻译，但也发现FMR1的5'前导序列含有一个隐蔽启动子，这可能会混淆对这些结果的解释。然而，在体外或体内对双顺反子和单顺反子RNA进行转染证实FMR1的5'前导序列含有一个IRES。此外，在体外抑制帽依赖性翻译并不影响内源性FMRP的表达水平，这表明FMR1 mRNA的IRES依赖性翻译发挥了作用。对FMR1的5'前导序列进行分析发现，CGG重复序列和前导序列的5'末端对于内部起始至关重要。在功能上，分别暴露于氯化钾或细胞内酸化以及添加聚肌苷酸:聚胞苷酸作为神经活动和双链RNA的模拟物，对FMR1 IRES活性有不同影响。

结论

我们的结果表明，多种刺激影响FMR1 mRNA的IRES依赖性翻译，并提示CGG核苷酸重复序列具有功能作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/53d5c9a1520a/1471-2199-9-89-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/ef2fe45180b3/1471-2199-9-89-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/2182efc5e600/1471-2199-9-89-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/463bbfd18e24/1471-2199-9-89-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/29d30c586f82/1471-2199-9-89-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/0614e7be2b15/1471-2199-9-89-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/53d5c9a1520a/1471-2199-9-89-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/ef2fe45180b3/1471-2199-9-89-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/2182efc5e600/1471-2199-9-89-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/463bbfd18e24/1471-2199-9-89-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/29d30c586f82/1471-2199-9-89-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/0614e7be2b15/1471-2199-9-89-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f04d/2576346/53d5c9a1520a/1471-2199-9-89-6.jpg

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