Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites.
Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites.
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DOI：
10.1093/nar/gks520
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发表时间：
2012-09
影响因子：
14.9
通讯作者：
Mayeda A
中科院分区：
文献类型：
--
作者：
Kameyama T;Suzuki H;Mayeda A
人类肿瘤易感基因101（TSG 101）的转录本在许多癌症中被异常剪接。TSG101前体mRNA上的一个主要异常剪接事件涉及外显子2和外显子9内分别连接远端选择性5′和3′剪接位点，导致mRNA的广泛消除。可变剪接位点的估计强度远低于真实剪接位点的强度。我们观察到，乳腺癌细胞中异位表达的无内含子TSG 101基因可以产生同等的异常mRNA。值得注意的是，我们鉴定了仅由外显子序列组成的途径特异性内源性IRNA，预测其通过剪接的mRNA上的外显子2和外显子9之间的再剪接产生。我们的研究结果提供了两步剪接途径的证据，其中最初的组成性剪接删除所有14个真实的剪接位点，从而使弱的选择性剪接位点接近。我们还证明了癌细胞中脆性组氨酸三联体（FHIT）前体mRNA的异常多外显子跳跃通过剪接的FHIT mRNA的再剪接发生。成熟mRNA的重新剪接可以潜在地在癌症转录组中产生突变非依赖性多样性。相反，在正常细胞中可能存在一种机制来防止潜在有害的mRNA再剪接事件。
Transcripts of the human tumor susceptibility gene 101 (TSG101) are aberrantly spliced in many cancers. A major aberrant splicing event on the TSG101 pre-mRNA involves joining of distant alternative 5′ and 3′ splice sites within exon 2 and exon 9, respectively, resulting in the extensive elimination of the mRNA. The estimated strengths of the alternative splice sites are much lower than those of authentic splice sites. We observed that the equivalent aberrant mRNA could be generated from an intron-less TSG101 gene expressed ectopically in breast cancer cells. Remarkably, we identified a pathway-specific endogenous lariat RNA consisting solely of exonic sequences, predicted to be generated by a re-splicing between exon 2 and exon 9 on the spliced mRNA. Our results provide evidence for a two-step splicing pathway in which the initial constitutive splicing removes all 14 authentic splice sites, thereby bringing the weak alternative splice sites into close proximity. We also demonstrate that aberrant multiple-exon skipping of the fragile histidine triad (FHIT) pre-mRNA in cancer cells occurs via re-splicing of spliced FHIT mRNA. The re-splicing of mature mRNA can potentially generate mutation-independent diversity in cancer transcriptomes. Conversely, a mechanism may exist in normal cells to prevent potentially deleterious mRNA re-splicing events.
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影响因子：
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