INHIBITION OF DNA REPLICATION BY DNA DAMAGING DRUGS

描述：许多不同类型的破坏DNA的药物被用作 化疗药物。这些药物造成的DNA损伤会导致 治疗作用机制尚不完全明了(S) 尽管抑制DNA复制被广泛认为是一种潜在的 机制。我们的目标是开发抑制DNA的范例 由破坏DNA的抗癌药物引起的复制。该方法利用 明确定义的细胞内猿猴病毒40和EB病毒DNA 确定是否通过限制数量的方法抑制DNA复制 DNA损伤剂具有特定的和充分描述的机制 动作发生在起始、延伸或两者兼而有之的层面，无论是 抑制通过顺式或反式机制发生。细胞的鉴定 有助于抑制DNA复制的蛋白质，可能 包括那些参与细胞周期检查站的人，将被寻求。这个 具体目标如下：目标1.鉴定破坏DNA的药物 它们在起始水平上抑制DNA复制的能力， 伸长或两者兼而有之。目标2.表征破坏DNA的药物 抑制顺式或反式DNA复制的能力。 目的3.研究反式DNA损伤剂的作用机制(S) 抑制复制。

DESCRIPTION: Many different types of DNA-damaging drugs are used as chemotherapeutic agents. The DNA damage caused by these drugs leads to therapeutic effects through as yet incompletely characterized mechanism(s) although inhibition of DNA replication is widely recognized as a potential mechanism. Our goal is to develop paradigms for inhibition of DNA replication caused by DNA-damaging anticancer drugs. The approach utilizes well-defined intracellular Simian Virus 40 and Epstein-Barr Virus DNA to determine whether inhibition of DNA replication by a limited number of DNA-damaging agents with specific and well-characterized mechanisms of action occurs at the level of initiation, elongation or both and whether inhibition occurs via cis or trans mechanisms. Identification of cellular proteins contributing to the inhibition of DNA replication, possibly including those involved in cell cycle checkpoints, will be sought. The specific aims are as follows: Aim 1. Characterize DNA-damaging drugs for their ability to inhibit DNA replication a the level of initiation, elongation or both. Aim 2. Characterize DNA-damaging drugs for their ability to inhibit DNA replication in cis or trans. Aim 3. Characterize mechanism(s) by which trans-acting DNA-damaging agents inhibit replication.