FUNCTIONAL ANALYSIS OF RAD23 PROTEIN

我们已经发现，DNA修复蛋白Rad 23具有蛋白水解作用， 功能这里提出的研究与辐射有广泛的相关性 生物学，并能对分子理解做出巨大贡献 从酵母到人类的核苷酸切除修复。 泛素/蛋白酶体途径是降解许多关键蛋白质所必需的。 真核细胞中的调节子。这一途径的目标包括重要的 细胞周期调节因子、转录因子、肿瘤抑制因子，以及 信号转导分子。我们的初步发现揭示了 核苷酸切除修复中的蛋白质降解; i）我们发现Rad 23具有 蛋白水解功能ii）Rad 23被Rad 53激酶磷酸化， 介导DNA损伤诱导检查点。iii）特异性泛素缀合 (E2)酶，包括DNA修复蛋白Rad 6，与 蛋白体这些研究为研究 DNA修复中的蛋白质降解。 在这个补助金申请中解决的问题可以产生新的， 关于Rad 23的蛋白水解功能的有趣信息。这些研究可以 也增加了我们对底物靶向机制的理解， E2/蛋白酶体相互作用的意义。的后果 Rad 23/蛋白酶体在DNA修复中的相互作用将被研究。 我们的研究增加了意义，因为Rad 23的人类同源物是 功能上类似于它们的酵母对应物。潜在的缺陷 几种人类疾病，包括着色性干皮病和科凯恩氏病， 综合征，涉及核苷酸切除修复途径。本 了解核苷酸切除修复和泛素介导的蛋白水解 已经发展得很好，我们现在有能力形成一个连贯的模型， 描述了这两种途径之间的联系。

We have discovered that the DNA repair protein Rad23 has a proteolytic function. The studies proposed here have broad relevance to radiation biology, and can make a strong contribution to a molecular understanding of nucleotide excision-repair from yeast to humans. The ubiquitin/proteosome pathway is required for the degradation of many key regulators in eukaryotic cells. The targets of this pathway include important cell-cycle regulators, transcription factors, tumor suppressors, and signal-transducing molecules. Our preliminary findings revealed a role for protein degradation in nucleotide excision-repair; i) we found that Rad23 has a proteolytic function. ii) Rad 23 is phosphorylated by the Rad53 kinase, which mediates a DNA damage-inducible checkpoint. iii) Specific ubiquitin-conjugating (E2) enzymes, including the DNA repair protein Rad6, interact with the proteosome. These studies provide a strong foundation for studying the role of protein degradation in DNA repair. The questions that are addressed in this Grant Application can yield new and interesting information on the proteolytic function of Rad23. These studies can also increase our understanding of the mechanisms of substrate targeting, and the significance of E2/proteasome interaction. The consequence of Rad23/proteasome interaction in DNA repair will be investigated. Our studies have added significance because the human homologs of Rad23 are functionally similar to their yeast counterpart. An underlying defect in several human diseases, including xeroderma pigmentosum and Cockayne's syndrome, involves the nucleotide excision-repair pathway. The present understanding of nucleotide excision-repair and ubiquitin-mediated proteolysis is well developed, and we now have the ability to form a coherent model that describes the link between these two pathways.