INHIBITION OF DNA REPLICATION BY DNA DAMAGING DRUGS

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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.