Identity and Functions of Selenoprotein Genes

说明（由申请人提供）：硒是一种重要的微量元素，具有显著的健康益处。它在免疫系统，男性生殖和许多其他生物系统和过程中具有有效的癌症预防活性和作用。这些硒的作用大多由含硒半胱氨酸（Sec）的蛋白质介导。然而，关于这些蛋白质的信息很少。Sec是遗传密码中的第21个氨基酸，与UGA密码子协同插入蛋白质中。硒蛋白的鉴定和功能分析具有挑战性。由于UGA密码子通常作为终止信号，硒蛋白基因在基因组注释中被错误注释或完全遗漏。在上一个资助周期中，我们开发了生物信息学工具，通过搜索保守的RNA结构（称为Sec插入序列（SECIS）元件）和识别含硒半胱氨酸/半胱氨酸的蛋白质对同源物来识别硒蛋白基因。通过使用这些工具，我们能够表征在许多完全测序的基因组（包括人类基因组）中编码的硒蛋白组（生物体中的整套硒蛋白）。我们还提供了实验证据的发生，新发现的硒蛋白和确定功能的几个硒蛋白使用计算和实验方法。当前应用的主要焦点是功能性地表征哺乳动物硒蛋白。该研究将由三个具体目标指导：1）在完全测序的基因组和基因组调查项目中鉴定硒蛋白基因，证明它们的发生，并分析多态性; 2）新鉴定的哺乳动物硒蛋白的功能表征，重点是它们的相互作用伙伴; 3）使用模型系统分析硒蛋白功能。PI先前的数据确定，它是可行的，以确定所有或几乎所有的硒蛋白基因编码的完全测序的基因组和功能特性的硒蛋白的特别感兴趣。产生的结果应该有助于解释许多生物学和生物医学的影响，膳食硒，硒代半胱氨酸的演变提供见解，并确定具有氧化还原功能的蛋白质。

DESCRIPTION (provided by applicant): Selenium is an essential trace element with significant health benefits. It has potent cancer prevention activity and roles in the immune system, male reproduction, and many other biological systems and processes. Most of these selenium's effects are mediated by selenocysteine (Sec)-containing proteins. However, information about these proteins is scarce. Sec is known as the 21st amino acid in the genetic code and is co-translationally inserted into proteins in response to UGA codon. Identification and functional analysis of selenoproteins are challenging. Because UGA codon normally serves as a stop signal, selenoprotein genes are misannotated or completely missed in genome annotations. In the previous funding cycle, we developed bioinformatics tools that allow identification of selenoprotein genes by searching for conserved RNA structures, called Sec insertion sequence (SECIS) elements, and identifying selenocysteine/cysteine-containing protein pairs of homologs. By using these tools, we were able to characterize selenoproteomes (entire sets of selenoproteins in an organism) encoded in many completely sequenced genomes, including the human genome. We also provided experimental evidence for the occurrence of newly identified selenoproteins and determined functions of several selenoproteins using computational and experimental approaches. The major focus of the current application is to functionally characterize mammalian selenoproteins. The proposed study will be guided by three specific aims: 1) identification of selenoprotein genes in completely sequenced genomes and genome survey projects, demonstration of their occurrence, and analyses of polymorphisms; 2) functional characterization of newly identified mammalian selenoproteins with the focus on their interaction partners; and 3) analysis of selenoprotein functions using model systems. The PI's previous data establish that it is feasible to identify all or almost all selenoprotein genes encoded in completely sequenced genomes and to functionally characterize selenoproteins of particular interest. The results generated should help explain many biological and biomedical effects of dietary selenium, provide insights into evolution of selenocysteine, and identify proteins with redox function.