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Evolutionary Emergence of a Novel Splice Variant with an Opposite Effect on the Cell Cycle

机译：对细胞周期有相反作用的新型剪接变体的进化出现。

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Alternative splicing contributes greatly to the diversification of mammalian proteomes, but the molecular basis for the evolutionary emergence of splice variants remains poorly understood. We have recently found a novel class of splicing regulatory elements between the polypyrimidine tract (Py) and 3′ AG (REPA) at intron ends in many human genes, including the multifunctional PRMT5 (for protein arginine methyltransferase 5) gene. The PRMT5 element is comprised of two G tracts that arise in most mammals and accompany significant exon skipping in human transcripts. The G tracts inhibit splicing by recruiting heterogeneous nuclear ribonucleoprotein (hnRNP) H and F (H/F) to reduce U2AF65 binding to the Py, causing exon skipping. The resulting novel shorter variant PRMT5S exhibits a histone H4R3 methylation effect similar to that seen with the original longer PRMT5L isoform but exhibits a distinct localization and preferential control of critical genes for cell cycle arrest at interphase in comparison to PRMT5L. This report thus provides a molecular mechanism for the evolutionary emergence of a novel splice variant with an opposite function in a fundamental cell process. The presence of REPA elements in a large group of genes implies their wider impact on different cellular processes for increased protein diversity in humans.
机译：选择性剪接极大地促进了哺乳动物蛋白质组的多样化，但是对于剪接变体进化出现的分子基础仍然知之甚少。我们最近在许多人类基因的内含子末端的多嘧啶束（Py）和3'AG（REPA）之间发现了一类新型的调控元件，包括多功能 PRMT5 （用于蛋白质精氨酸甲基转移酶5 ）基因。 PRMT5元件由大多数哺乳动物中出现的两个G道组成，并伴有人类转录本中显着的外显子跳跃。 G线通过募集异质核糖核蛋白（hnRNP）H和F（H / F）来减少剪接，从而减少U2AF65与Py的结合，从而导致外显子跳跃。所得的新颖的较短变体PRMT5S表现出与最初的较长PRMT5L同工型相似的组蛋白H4R3甲基化作用，但与PRMT5L相比，表现出对细胞周期停滞的关键基因的独特定位和优先控制。因此，该报告提供了在基本细胞过程中具有相反功能的新型剪接变体进化出现的分子机制。 REPA元素在大量基因中的存在意味着它们对人类增加蛋白质多样性的不同细胞过程的广泛影响。

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