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阐明 U2AF1 上的癌症相关突变对异常 3' 剪接位点选择的影响。

Elucidation of the aberrant 3' splice site selection by cancer-associated mutations on the U2AF1.

机构信息

Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.

Department of Biochemistry, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, 693-8501, Japan.

出版信息

Nat Commun. 2020 Sep 21;11(1):4744. doi: 10.1038/s41467-020-18559-6.

DOI:10.1038/s41467-020-18559-6
PMID:32958768
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7505975/
Abstract

The accurate exclusion of introns by RNA splicing is critical for the production of mature mRNA. U2AF1 binds specifically to the 3´ splice site, which includes an essential AG dinucleotide. Even a single amino acid mutation of U2AF1 can cause serious disease such as certain cancers or myelodysplastic syndromes. Here, we describe the first crystal structures of wild-type and pathogenic mutant U2AF1 complexed with target RNA, revealing the mechanism of 3´ splice site selection, and how aberrant splicing results from clinically important mutations. Unexpected features of this mechanism may assist the future development of new treatments against diseases caused by splicing errors.

摘要

准确排除内含子是 RNA 剪接产生成熟 mRNA 的关键。U2AF1 特异性结合 3'剪接位点，其中包括一个必需的 AG 二核苷酸。U2AF1 的单个氨基酸突变甚至可以导致严重的疾病，如某些癌症或骨髓增生异常综合征。在这里，我们描述了野生型和致病性突变 U2AF1 与靶 RNA 复合物的首个晶体结构，揭示了 3'剪接位点选择的机制，以及临床重要突变如何导致异常剪接。该机制的一些意外特征可能有助于未来开发针对由剪接错误引起的疾病的新治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/4ca329ee9b8f/41467_2020_18559_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/825d0b0a579e/41467_2020_18559_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/068581fa366c/41467_2020_18559_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/2ffcf5959d2e/41467_2020_18559_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/a433bb2aeeaf/41467_2020_18559_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/4ca329ee9b8f/41467_2020_18559_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/825d0b0a579e/41467_2020_18559_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/068581fa366c/41467_2020_18559_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/2ffcf5959d2e/41467_2020_18559_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/a433bb2aeeaf/41467_2020_18559_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b73c/7505975/4ca329ee9b8f/41467_2020_18559_Fig5_HTML.jpg

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