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首页> 外文学位 >Eya: A dual function nuclear factor crucial for regulation of developmental gene expression and prevention of apoptosis in response to genotoxic stress.
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Eya: A dual function nuclear factor crucial for regulation of developmental gene expression and prevention of apoptosis in response to genotoxic stress.

机译：Eya：双重功能的核因子，对于调节遗传基因应激反应中发育基因的表达和防止细胞凋亡至关重要。

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摘要

The developmentally regulated nuclear factors of the Eya family function in transcriptional regulation of developmental genes and have been recently characterized as tyrosine phosphatases. Eya is a component of the retinal determination gene network, which is crucial for the development of multiple organ systems in mammals, with loss of Eya leading to increased apoptosis and organ agenesis. While phosphatase activity is important for proper organ development, lack of confirmed substrates for Eya phosphatase activity has prevented a deeper understanding of Eya's function. We sought to identify phosphatase substrates for Eya using multiple strategies including biochemical purification, transcriptional assays, and candidate testing. Contrary to initial assumptions, the phosphatase activity of Eya was dispensable for transcriptional activation of the Eya target gene Sall1 and transcriptional activation was wholly mediated by the N-terminal transactivation domain. We found that the phosphatase activity of Eya functions in a non-transcriptional context, by preventing apoptotic death under conditions of genotoxic stress. Under DNA damage conditions, Eya relocalizes within the nucleus to sites of DNA double strand breaks, where it interacts with the histone variant H2AX. H2AX is phosphorylated under basal conditions on tyrosine 142, a mark that is directly removed by Eya as part of the DNA damage response. H2AX is known to become phosphorylated on serine 139 early in the DNA damage response, and this phosphoserine mark serves as a binding surface for various DNA repair proteins, including MDC1. Persistent phosphorylation of tyrosine 142 in the absence of Eya leads to increased cellular apoptosis in response to genotoxic stress due to differential binding of apoptotic versus repair complexes to the phosphorylated tail of H2AX. Thus, in the context of the DNA damage response, Eya possesses a novel anti-apoptotic function that is dependent on phosphatase activity. We propose that in-vivo Eya exists as a dual-function nuclear factor, activating a transcriptional program as a component of the retinal determination network in basal conditions and dephosphorylating H2AX on tyrosine 142 as a component of the DNA damage response under conditions of genotoxic stress.
机译：Eya家族的受发育调节的核因子在发育基因的转录调节中起作用，最近被表征为酪氨酸磷酸酶。 Eya是视网膜测定基因网络的一个组成部分，对于哺乳动物多器官系统的发育至关重要，Eya的丧失导致细胞凋亡和器官发育不全。虽然磷酸酶活性对于适当的器官发育很重要，但是缺乏确凿的Eya磷酸酶活性底物阻碍了人们对Eya功能的更深入了解。我们力图使用多种策略（包括生化纯化，转录测定和候选测试）来鉴定Eya的磷酸酶底物。与最初的假设相反，Eya的磷酸酶活性对于Eya目标基因Sall1的转录激活是必不可少的，并且转录激活完全由N末端反式激活域介导。我们发现Eya的磷酸酶活性在非转录的情况下，通过防止在遗传毒性应激条件下的凋亡死亡而起作用。在DNA损伤的条件下，Eya在细胞核内重新定位到DNA双链断裂的位点，并与组蛋白变体H2AX相互作用。 H2AX在碱性条件下在酪氨酸142上被磷酸化，酪氨酸作为DNA损伤反应的一部分被Eya直接去除。已知H2AX在DNA损伤反应的早期会在丝氨酸139上被磷酸化，该磷酸丝氨酸标记可作为包括MDC1在内的各种DNA修复蛋白的结合表面。在不存在Eya的情况下，酪氨酸142的持续磷酸化导致细胞凋亡增加，这是由于细胞凋亡与修复复合物与H2AX磷酸化尾部的不同结合而导致的遗传毒性应激。因此，在DNA损伤反应的背景下，Eya具有依赖于磷酸酶活性的新型抗凋亡功能。我们提出体内Eya作为双重功能核因子存在，在基础条件下激活转录程序作为视网膜测定网络的组成部分，并在遗传毒性胁迫条件下将酪氨酸142上的H2AX脱磷酸化作为DNA损伤反应的组成部分。

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  • 作者

    Cook, Peter Joseph.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 142 p.
  • 总页数 142
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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