Regulation of human telomerase splicing by RNA:RNA pairing.
Regulation of human telomerase splicing by RNA:RNA pairing.
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DOI：
10.1038/ncomms4306
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发表时间：
2014-02-28
影响因子：
16.6
通讯作者：
Wright, Woodring E.
中科院分区：
文献类型：
--
作者：
Wong, Mandy S.;Shay, Jerry W.;Wright, Woodring E.
端粒酶将端粒重复序列添加到染色体末端，并且在人类癌症中几乎普遍上调。在这里，我们证明，RNA：RNA配对调节剪接的催化亚基的人端粒酶（TERT）。人类等位基因在TERT内含子6内含有可变数量的38 bp重复序列（距离外显子-内含子连接处>1 kb）。至少需要9个重复序列来产生主要的非功能性“负β”同种型，其跳过外显子7和8。RNA：重复序列和前体mRNA之间的RNA配对可能使外显子6和9更接近，从而促进外显子跳跃。为了证明这一点，我们证明了重复序列中废除外显子跳跃的突变可以通过前mRNA中的补偿突变来纠正。因此，这项研究将重复序列的RNA：RNA配对确定为对癌症生存至关重要的基因中的一种新形式的选择性剪接调控，并为嵌入整个基因组内含子深处的短重复序列的功能作用提供了新的见解。 端粒酶催化亚基TERT的选择性剪接可调控端粒酶活性。在这里，Wong等人证明，通过重复内含子序列与前体mRNA的RNA：RNA配对来调节TERT剪接，从而揭示了嵌入内含子内的保守元件的新功能。
Telomerase adds telomeric repeats onto chromosome ends and is almost universally upregulated in human cancers. Here we demonstrate that RNA:RNA pairing regulates splicing of the catalytic subunit of human telomerase (TERT). Human alleles contain a variable number of 38 bp repeats within TERT intron 6 (>1 kb from exon–intron junctions). At least nine repeats are required for generating the major non-functional ‘minus beta’ isoform, which skips exons 7 and 8. RNA:RNA pairing between the repeats and the pre-mRNA might bring exons 6 and 9 closer, thereby promoting exon skipping. To demonstrate this, we show that mutations within the repeat that abolish exon skipping are corrected by compensatory mutations in the pre-mRNA. This study thus identifies RNA:RNA pairing by repetitive sequences as a novel form of alternative splicing regulation in a gene crucial for cancer survival and sheds new light on functional roles for short repetitive sequences embedded deep within introns throughout the genome. Telomerase activity can be regulated by alternative splicing of its catalytic subunit TERT. Here, Wong et al. demonstrate that TERT splicing is regulated via RNA:RNA pairing of repetitive intronic sequences with the pre-mRNA, thus revealing a new function for conserved elements embedded within introns.
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