DNA TRANSACTIONS AND GENOME INTEGRITY IN AGING

该提案包括一套六个研究项目，这些项目形成了一个连贯的 以及理解倾向于改变基因组的过程的综合努力 结构和组织，以及细胞拥有的促进， 抵制和修复这样的修改。因为这些过程是 毫无疑问，对于细胞和有机体的生存来说，我们认为 它们可能在细胞和生物衰老过程中起着重要作用。因此， 该计划项目的一个主要目标是描述参与者的特征 和部分DNA交易的分子机制，并探索它们的 状态和可能与老化过程的相关性。个人 项目的重点是： 1.通过重组修复双链断裂和缺失 哺乳动物细胞， 2.染色体复制的调控及其对频率的影响 染色体断裂，重组丢失和不分离， 3.评估DNA损伤和修复在衰老现象中的作用 对与发育或年龄有关的因素的研究，这些因素解释了 脑内不同区域DNA损伤可修复性的差异 终末分化细胞的基因组， 4.对HIGHERY的复制和纠错过程的分析 纯化的复制系统，以期建立分析和 老化过程中评估复制保真度的标准， 5.决定基因组完整性的因素：正常的复制保真度 单纯疱疹病毒DNA聚合酶对DNA的损伤作用及其机制 同源序列间的定点分子内重组 由最近检测到的一种哺乳动物酶催化， 6.导致组装的基因组重排的机制 功能性免疫球蛋白重链和轻链，特别是开关 将重链可变区连接到五个中的任何一个的重组 恒定区域。

This proposal includes a set of six research projects which form a coherent and integrated effort to understand the processes tending to alter genome structure and organization, and the mechanisms cells possess to promote, resist and repair such modifications. Because these processes are undoubtedly fundamental to cell and organismal survival, we presume that they may be important in cellular and organismal senescence. Accordingly, a principal aim of this program project is to characterize the participants and molecular mechanisms of selected DNA transactions, and to explore their status and possible relevance to the aging process. The individual projects focus on: 1. repair of double strand breaks and deletions by recombination in mammalian cells, 2. regulation of chromosomal replication and its influence on the frequency of chromosome breakage, recombinational loss and nondisjunction, 3. an assessment of the role of DNA damage and repair in aging phenomena by studies of the developmental or age-related factors which account for the variation in the repairability of DNA damage in different regions of the genome of terminally differentiated cells, 4. an analysis of the replication and error-correction processes in highly purified replication systems with a view toward establishing assays and criteria for evaluating replication fidelity during aging processes, 5. factors governing genome integrity: the replication fidelity of normal and damaged DNA by Herpes Simplex DNA polymerase, and the mechanism of site-specific intramolecular recombination between homologous sequences catalyzed by a recently detected mammalian enzyme, 6. the mechanism of genome rearrangements leading to the assembly of functional immunoglobin heavy and light chains, particularly the switch recombinations that link a heavy chain variable region to any one of five constant regions.