DNA REPAIR IN NORMAL AND MUTATION-PRONE SEQUENCES
正常和易突变序列中的 DNA 修复
基本信息
- 批准号:3438909
- 负责人:
- 金额:$ 9.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1990
- 资助国家:美国
- 起止时间:1990-04-01 至 1993-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DNA is damaged by many chemical and physical environmental agents. Most
damage is removed by one of the cellular DNA repair systems, but some
persistent damage blocks DNA replication or causes errors in DNA
replication, leading to mutations and altered function. Is the persistence
of this damage the result of random oversight by the repair systems or does
it reflection fundamental properties of the damaged site? In the bacterium
Escherichia coli, most large bulky adducts are repaired by the uvr system,
including adducts formed by N-acetoxy-N-acetyl-2-aminofluorene (-AAF) and
N-hydroxy-N-2-aminofluorene (-AF). However, indirect evidence suggests
that -AAF adducts within certain mutation-prone sequences are poorly
repaired. The presence of the adduct in these sequences may induce a
localized transition to Z-form DNA.
In this project, the interaction of the UvrABC proteins with -AAF adducts
and -AF adducts in mutation-prone and normal sequences will be examined
directly in vitro. High resolution gel electrophoresis will be combined
with specific chemical and enzymatic reactions to determine quantitatively
the sequence distribution of DNA damage, UvrA binding and UvrABC incision.
This method will allow sequence-specific adduct structures that interact
unusually with the repair system to be identified and will allow an
exploration of the underlying structural features. The sensitivity of DNA
conformational transitions to variation in the nature and concentration of
salts in the solution will be exploited to probe the physical basis for
altered interactions with the repair proteins.
Although the Uvr system uses distortion in the DNA helix to detect damage,
only a specific form of distortion may be recognized. Damage inducing
unusual distortions in the DNA may escape detection by the repair system.
Since the Uvr system of Escherichia coli has elements in common with repair
systems in higher organisms, the results of this study may illuminate
specific connections between the persistence of damage in DNA, DNA repair
and mutagenesis or carcinogenesis.
DNA 会受到许多化学和物理环境因素的损害。 最多
损伤可以通过细胞 DNA 修复系统之一消除,但有些
持续性损伤会阻碍 DNA 复制或导致 DNA 错误
复制,导致突变和功能改变。 是坚持
这种损坏是修复系统随机疏忽的结果,或者确实
它反映了受损部位的基本特性吗? 在细菌中
大肠杆菌,大多数大体积的加合物都被紫外线系统修复,
包括由 N-乙酰氧基-N-乙酰基-2-氨基芴 (-AAF) 形成的加合物和
N-羟基-N-2-氨基芴(-AF)。 然而,间接证据表明
某些易突变序列中的-AAF 加合物效果很差
修复了。 这些序列中加合物的存在可能会诱导
局部转变为 Z 型 DNA。
在这个项目中,UvrABC 蛋白与 -AAF 加合物的相互作用
将检查易突变序列和正常序列中的 -AF 加合物
直接在体外。 将高分辨率凝胶电泳结合起来
通过特定的化学和酶反应来定量测定
DNA损伤、UvrA结合和UvrABC切口的序列分布。
该方法将允许相互作用的序列特异性加合物结构
修复系统异常被识别,并且将允许
探索潜在的结构特征。 DNA的敏感性
构象转变导致性质和浓度的变化
将利用溶液中的盐来探究其物理基础
改变与修复蛋白的相互作用。
尽管 Uvr 系统利用 DNA 螺旋的扭曲来检测损伤,
只能识别特定形式的失真。 伤害诱发
DNA 中异常的扭曲可能会逃避修复系统的检测。
由于大肠杆菌的 Uvr 系统与修复有共同点
高等生物系统,这项研究的结果可能会阐明
DNA 损伤持续性与 DNA 修复之间的特定联系
和诱变或致癌作用。
项目成果
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