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一种新型 HPV16 剪接增强子，对病毒癌基因表达和细胞永生化至关重要。

A novel HPV16 splicing enhancer critical for viral oncogene expression and cell immortalization.

机构信息

Department of Medical Biochemistry and Microbiology, Uppsala University, BMC-B9, 751 23 Uppsala, Sweden.

Center of Translational Medicine, Zibo Central Hospital, 255036 Zibo, China.

出版信息

Nucleic Acids Res. 2024 Jan 11;52(1):316-336. doi: 10.1093/nar/gkad1099.

DOI:10.1093/nar/gkad1099
PMID:37994701
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10783526/
Abstract

High-risk carcinogenic human papillomaviruses (HPVs), e.g. HPV16, express the E6 and E7 oncogenes from two mRNAs that are generated in a mutually exclusive manner by splicing. The HPV16 E7 mRNA, also known as the E6I/E7 mRNA, is produced by splicing between splice sites SD226 and SA409, while E6 mRNAs retain the intron between these splice sites. We show that splicing between HPV16 splice sites SD226 and SA409 is controlled by a splicing enhancer consisting of a perfect repeat of an adenosine-rich, 11 nucleotide sequence: AAAAGCAAAGA. Two nucleotide substitutions in both 11 nucleotide sequences specifically inhibited production of the spliced E6I/E7 mRNA. As a result, production of E7 protein was reduced and the ability of HPV16 to immortalize human primary keratinocytes was abolished. The splicing-enhancing effect was mediated by the cellular TRAP150/THRAP3 protein that also enhanced splicing of other high-risk HPV E6*I/E7 mRNAs, but had no effect on low-risk HPV mRNAs. In summary, we have identified a novel splicing enhancer in the E6 coding region that is specific for high-risk HPVs and that is critically linked to HPV16 carcinogenic properties.

摘要

高危致癌型人乳头瘤病毒（HPV），例如 HPV16，通过剪接从两个 mRNA 中表达 E6 和 E7 癌基因，这两个 mRNA 以相互排斥的方式生成。HPV16 E7 mRNA，也称为 E6I/E7 mRNA，是通过在剪接位点 SD226 和 SA409 之间的剪接产生的，而 E6 mRNAs 保留了这些剪接位点之间的内含子。我们表明，HPV16 剪接位点 SD226 和 SA409 之间的剪接由一个包含腺苷丰富的 11 个核苷酸序列完美重复的剪接增强子控制：AAAAGCAAAGA。这两个 11 个核苷酸序列中的两个核苷酸取代特异性地抑制了剪接的 E6I/E7 mRNA 的产生。结果，E7 蛋白的产生减少，HPV16 使人类原代角质形成细胞永生化的能力被废除。剪接增强子由细胞 TRAP150/THRAP3 蛋白介导，该蛋白还增强了其他高危 HPV E6*I/E7 mRNAs 的剪接，但对低危 HPV mRNAs 没有影响。总之，我们在 E6 编码区中鉴定出一种新的剪接增强子，该增强子对高危 HPV 具有特异性，并且与 HPV16 的致癌特性密切相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/aa0b7325bbcd/gkad1099fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/f09297bb2cb7/gkad1099figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/c15c5ba70da4/gkad1099fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/7f2f3f2177c6/gkad1099fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/2c9f1cfdb71f/gkad1099fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/9b03a67fd52c/gkad1099fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/62cf15b24895/gkad1099fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/c87a86968dc4/gkad1099fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/8dc6220a15f2/gkad1099fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/aa0b7325bbcd/gkad1099fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/f09297bb2cb7/gkad1099figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/c15c5ba70da4/gkad1099fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/7f2f3f2177c6/gkad1099fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/2c9f1cfdb71f/gkad1099fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/9b03a67fd52c/gkad1099fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/62cf15b24895/gkad1099fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/c87a86968dc4/gkad1099fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/8dc6220a15f2/gkad1099fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7062/10783526/aa0b7325bbcd/gkad1099fig8.jpg

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