RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events.
RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events.
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DOI：
10.1093/nar/gkm447
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发表时间：
2007
影响因子：
14.9
通讯作者：
Baralle FE
中科院分区：
文献类型：
--
作者：
Buratti E;Dhir A;Lewandowska MA;Baralle FE
越来越多的报道称，前体mRNA分子内含子区域深处的基因组变异会影响剪接事件。然而，没有一般性的解释，为什么明显相似的变化可能对剪接没有影响或导致显着的剪接改变。在这项工作中，我们已经研究了以前描述的ATM和CFTR患者的假外显子的结构架构。ATM病例源自阻遏元件的缺失，其特征在于尽管存在更好的替代物，但仍存在异常的5′ss选择。相反，CFTR假外显子来源于一个新的5′ss的产生，该5′ss被使用，而附近的预先存在的供体样序列从未被选择。我们的研究结果表明，RNA结构是一个主要的剪接调节因子在这两种情况下。此外，原始RNA结构的操作可以导致假外显子包含后暴露未使用的5′ss已经存在于其野生型内含子序列中，并防止被识别，因为它们的位置在RNA茎结构。我们的数据表明，必须考虑内含子的内在结构特征，以了解遗传性疾病中假外显子激活的机制。我们的观察可能有助于改善诊断预测方案和最终的治疗靶向。
Genomic variations deep in the intronic regions of pre-mRNA molecules are increasingly reported to affect splicing events. However, there is no general explanation why apparently similar variations may have either no effect on splicing or cause significant splicing alterations. In this work we have examined the structural architecture of pseudoexons previously described in ATM and CFTR patients. The ATM case derives from the deletion of a repressor element and is characterized by an aberrant 5′ss selection despite the presence of better alternatives. The CFTR pseudoexon instead derives from the creation of a new 5′ss that is used while a nearby pre-existing donor-like sequence is never selected. Our results indicate that RNA structure is a major splicing regulatory factor in both cases. Furthermore, manipulation of the original RNA structures can lead to pseudoexon inclusion following the exposure of unused 5′ss already present in their wild-type intronic sequences and prevented to be recognized because of their location in RNA stem structures. Our data show that intrinsic structural features of introns must be taken into account to understand the mechanism of pseudoexon activation in genetic diseases. Our observations may help to improve diagnostics prediction programmes and eventual therapeutic targeting.
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