INHIBITION OF DNA REPLICATION BY DNA DAMAGING DRUGS

描述：许多不同类型的DNA损伤药物被用作 化疗剂。 这些药物造成的DNA损伤导致 通过尚未完全表征的机制实现的治疗效果 尽管DNA复制的抑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 明确的细胞内猿猴病毒40和EB病毒DNA， 确定是否抑制DNA复制的有限数量的 具有特异性和充分表征的DNA损伤机制的药物 作用发生在起始、延长或两者的水平， 通过顺式或反式机制发生抑制。 细胞识别 有助于抑制DNA复制的蛋白质，可能 包括参与细胞周期检查点的那些。 的 具体目标如下：目标1。 表征DNA损伤药物， 它们在起始水平上抑制DNA复制的能力， 伸长或两者。 目标二。 描述DNA损伤药物的特征， 抑制顺式或反式DNA复制的能力。 目标3： 描述反式作用DNA损伤剂的作用机制 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.