DROSOPHILA ANALOGUES OF HUMAN DNA REPAIR DEFICIENCIES

这一计划的最终目标是实现更彻底的 对高等生物用于争斗的机制的理解 与化学物质或辐射引起的DNA损伤有关。果蝇的分析 具有DNA修复缺陷的突变类似于已知的人类疾病 应该有助于增进对这些人类的理解 不足之处。对DNA修复的研究也将间接地推动我们的 了解突变和重组的过程。这个 这些研究的基础包括一组突变体，这些突变体 识别30多个可能在DNA中发挥作用的不同遗传基因座 修理。到目前为止，至少有一条主要修复途径存在缺陷 在其中13个基因座的突变体中被发现。这方面的下一步 分析将用生化方法剖析这些主要的修复途径 变种人的帮助阻止了。有两个问题被选为 集中研究：在这两种情况下，都发现了改变 对诱变侮辱的生物化学检测反应。在…的第一个 这些研究的关键修复酶无嘌呤/脱嘧啶核酸内切酶将 全面描述其特征，并结合以下内容分析其功能 基因研究。通过利用最近发现的酶缺陷 我们应该对突变股票的控制有一个更好的认识 以及这类酶的功能。将使用的一些突变体是 在形式上类似于人类遗传病的特定病例 色素性干皮病同时，我们将调查一系列 与人类疾病表现出互补表型的突变体 共济失调毛细血管扩张症。这两种生物的基因缺陷都会改变DNA 在未诱变的细胞中合成。在诱变细胞中，人类的疾病 对电离辐射没有正常反应，而果蝇 突变体对化学诱变剂的反应异常。果蝇突变体 因此代表了在 共济失调毛细血管扩张症。我们将采用生化和遗传相结合的方法 研究这一机制的方法。

The ultimate goal of this program is to achieve a more thorough understanding of the mechanisms employed by higher organisms to contend with DNA damage induced by chemicals or radiation. Analysis of Drosophila mutants with DNA repair deficiencies analogues to known human disorders should contribute to an increased understanding of those human deficiencies. Studies of DNA repair will also indirectly further our understanding of the processes of mutation and recombination. The foundation for these studies consists of a collection of mutants which identify over 30 different genetic loci that potentially play a role in DNA repair. Deficiencies in at least one major repair pathway have thus far been identified in mutants at 13 of these loci. The next step in this analysis will be to dissect these major repair pathways biochemically with the aid of the mutant blocks. Two problems have been selected for concentrated study: in both cases mutants have been identified which alter a biochemically detectable response to mutagenic insult. In the first of these studies the key repair enzyme apurinic/apyrimidinic endonuclease will be thoroughly characterized and its function analyzed in conjunction with genetic studies. By exploiting recently identified enzyme deficiencies in mutant stocks, we should achieve an improved understanding of the control and function of this enzyme class. Some of the mutants to be employed are formally analogous to selected cases of the human genetic disorder xeroderma pigmentosum. Simultaneously we will investigate a series of mutants which exhibit a complementary phenotype to the human disorder ataxia telangiectasia. The genetic defects in both organisms modify DNA synthesis in unmutagenized cells. In mutagenized cells the human disorder fails to respond normally to ionizing radiation, whereas the Drosophila mutants respond abnormally to chemical mutagens. The Drosophila mutants therefore represent a new variation of the defense mechanism identified in ataxia telangiectasia. We will employ a combined biochemical and genetic approach to investigate this mechanism.