Identity and Functions of Selenoprotein Genes

描述（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。硒的这些作用大多是由含硒半胱氨酸（Sec）的蛋白质介导的。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，响应UGA密码子共翻译插入到蛋白质中。硒蛋白的鉴定和功能分析具有挑战性。由于UGA密码子通常作为停止信号，硒蛋白基因在基因组注释中被错误注释或完全遗漏。在之前的资助周期中，我们开发了生物信息学工具，通过搜索称为Sec插入序列（SECIS）元件的保守RNA结构和鉴定含硒半胱氨酸/半胱氨酸的同源蛋白对来鉴定硒蛋白基因。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）。我们还为新发现的硒蛋白的出现提供了实验证据，并利用计算和实验方法确定了几种硒蛋白的功能。目前应用的主要焦点是哺乳动物硒蛋白的功能表征。该研究将以三个具体目标为指导：1)在全基因组测序和基因组调查项目中鉴定硒蛋白基因，证明其存在，并分析其多态性；2)新发现的哺乳动物硒蛋白的功能特征及其相互作用伙伴；3)利用模型系统分析硒蛋白的功能。PI先前的数据表明，鉴定完全测序基因组中编码的所有或几乎所有硒蛋白基因以及对特定硒蛋白进行功能表征是可行的。所产生的结果将有助于解释膳食硒的许多生物学和生物医学效应，为硒半胱氨酸的进化提供见解，并识别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.