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Repression of Prespliceosome Complex Formation at Two Distinct Steps by Fox-1/Fox-2 Proteins

机译：Fox-1 / Fox-2蛋白在两个不同的步骤抑制前剪接体复合物形成。

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Precise and robust regulation of alternative splicing provides cells with an essential means of gene expression control. However, the mechanisms that ensure the tight control of tissue-specific alternative splicing are not well understood. It has been demonstrated that robust regulation often results from the contributions of multiple factors to one particular splicing pathway. We report here a novel strategy used by a single splicing regulator that blocks the formation of two distinct prespliceosome complexes to achieve efficient regulation. Fox-1/Fox-2 proteins, potent regulators of alternative splicing in the heart, skeletal muscle, and brain, repress calcitonin-specific splicing of the calcitonin/CGRP pre-mRNA. Using biochemical analysis, we found that Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. First, Fox-1/Fox-2 proteins bind to the intronic site to inhibit SF1-dependent E′ complex formation. Second, these proteins bind to the exonic site to block the transition of E′ complex that escaped the control of the intronic site to E complex. These studies provide evidence for the first example of regulated E′ complex formation. The two-step repression of presplicing complexes by a single regulator provides a powerful and accurate regulatory strategy.
机译：精确和稳定的替代剪接调控为细胞提供了基因表达控制的必要手段。但是，对于确保严格控制组织特异性替代剪接的机制尚不清楚。已经证明，强有力的调节通常是由多种因素对一种特定的剪接途径的贡献引起的。我们在这里报告了一个新的策略，由单个剪接调节剂使用，它阻止了两个截然不同的前剪接体复合物的形成，以实现有效的调节。 Fox-1 / Fox-2蛋白是心脏，骨骼肌和大脑中选择性剪接的有效调节因子，可抑制降钙素/ CGRP前mRNA的降钙素特异性剪接。使用生化分析，我们发现Fox-1 / Fox-2蛋白通过结合两个功能上重要的UGCAUG元素，在两个不同的步骤中阻断了剪接体复合物的形成。首先，Fox-1 / Fox-2蛋白结合到内含子位点以抑制SF1依赖的E'复合物的形成。其次，这些蛋白质与外显子位点结合，阻止逃脱内含子位点控制的E'复合物向E复合物的转变。这些研究为调控E'复合物形成的第一个实例提供了证据。单个调节器可分两步抑制预先配制的配合物，提供了强大而准确的调节策略。

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