ABERRANT RNA PROCESSING IN HUMAN DEVELOPMENT

描述（根据申请人的描述改编）：本提案使用 结合生物化学和X射线晶体学方法来研究 遗传性疾病中RNA加工异常的结构基础。 CUG结合 蛋白（CUG-BP）、ELAV型RNA结合蛋白（ETR）-1和-3是蛋白质 负责在各种发育调节剪接位点的选择 组织和细胞类型。 这些蛋白质含有3个拷贝的RNA 识别基序（RRM），并参与广泛的RNA加工 事件包括剪接、转运和mRNA周转。 CUG-BP、ETR-1和 ETR-3特异性地影响横纹肌组织中的剪接位点选择。 CUG-BP首先与强直性肌营养不良（DM）有关， 一种遗传性疾病，是由一个基因组中CUG重复序列的扩增引起的。 肌紧张素激酶基因的非翻译区，并导致症状 出生时轻度肌强直至严重发育迟缓。DM是一种常见的 疾病（1/8000出生）。CUG-BP还与富含CUG的序列相互作用 在许多其他mRNA中发现。体内CUG-BP、ETR- 1或ETR-3导致剪接中的组织特异性变化， 发育或疾病相关的RNA加工缺陷。这个奖项 将被用来研究已经参与的RNA序列如何 核糖核蛋白复合物被其他RNA结合物读取或“扫描”， 蛋白质，如参与选择性剪接的蛋白质。晶体学 确定CUG-BP三维结构所需的条件， ETR-1和ETR-3使用x- 射线晶体学也将被确定。由此得出的结果 这一提议将大大拓宽我们对异常RNA 剪接发生并解决RNA代谢的基本方面， 为人类疾病领域的研究人员提供即时见解 发病机制

DESCRIPTION (Adapted from applicant's description): This proposal uses a combination of biochemical and x-ray crystallographic approaches to study the structural basis of aberrant RNA processing in genetic disease. CUG-binding protein (CUG-BP), ELAV-type RNA-binding protein (ETR) -1 and -3 are proteins responsible for developmentally regulated splice site selection in a variety of tissues and cell types. These proteins contain 3 copies of the RNA recognition motif (RRM) and participate in a wide range of RNA processing events including, splicing, transport and mRNA turnover. CUG-BP, ETR-1 and ETR-3 specifically effect splice site selection in striated muscle tissue. CUG-BP was first isolated in connection with myotonic dystrophy (DM), a genetic disease that results from an expansion of CUG repeats in an untranslated region of the myotonin kinase gene and results in symptoms from mild myotonia to severe retardation at birth. DM is an unfortunately common disease (1 in 8000 births). CUG-BP also interacts with CUG-rich sequences found in a number of other mRNAs. Alteration of in vivo levels of CUG-BP, ETR- 1 or ETR-3 result in tissue specific changes in splicing that appear to mimic either developmental or disease related RNA processing defects. This award would be used to examine how RNA sequences already involved in ribonucleoprotein complexes are read or "scanned" by other RNA binding proteins such as those involved in alternate splicing. Crystallographic conditions required to determine the three-dimensional structure of CUG-BP, ETR-1, and ETR-3 bound to their physiologically relevant RNA targets using x- ray crystallography will also be determined. The results derived from this proposal will significantly broaden our understanding of how aberrant RNA splicing occurs and address fundamental aspects of RNA metabolism to provide immediate insights to investigators working in the field of human disease pathogenesis.