MECHANISMS OF DNA DAMAGE TRIGGERED S PHASE CHECKPOINTS

DNA 损伤触发 S 相检查点的机制

• 批准号: 6833488
• 负责人: THOMAS MELENDY
• 金额: $ 33.17万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-12 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833488
• 关键词: DNA binding protein; DNA damage; DNA directed DNA polymerase; DNA replication; alkylating agents; antineoplastics; laboratory rabbit; phosphatidylinositol 3 kinase; phosphoproteins; posttranslational modifications; protein structure function; simian virus 40; virus DNA

DESCRIPTION (adapted from applicant's abstract): The goal of this research is to identify the mechanisms by which the S-phase DNA damage checkpoint responses arrest DNA replication. These checkpoints are the way cells temporarily stop passage through the cell cycle to allow time for repair of DNA damage, prior to cell division. If these checkpoints don't act appropriately, there are various possible outcomes. Minor DNA damage can lead to permanent mutations in the genome. Greater DNA damage can lead to chromosomal breakage, rearrangement, translocations, and even catastrophic cell division. The principal investigator's preliminary studies have shown that he can use an SV4O in vitro DNA replication system, which is supported predominantly by human cell extracts, to biochemically investigate S phase DNA damage dependent checkpoints. Pretreatment of cultured human cells with DNA damaging agents leads to inhibition of in vitro SV4O DNA replication that parallels the inhibition of chromosomal DNA replication in vivo. As model drugs, the principal investigator has chosen to use two anti-cancer chemotherapeutics. He has shown that these two drugs trigger different mechanisms for arresting DNA replication, adozelesin inactivates a known cellular DNA replication protein, RPA, while bizelesin induces the presence of a trans-acting DNA replication inhibitor. The goals of this proposal are to understand how adozelesin results in the inactivation of RPA, and to identify the trans-inhibitor induced by bizelesin, identify the replication protein that is the target of this trans-inhibitor, and to determine how this second mechanism results in the inhibition of DNA replication. During their progression, most forms of cancer have lost one or more of their DNA-damage checkpoint responses. This likely explains why most cancer therapies generally destroy cancer cells through catastrophic cell division. Elucidating these DNA-damage dependent checkpoint pathways and understanding the mechanisms of how they work, will ultimately aid in the design of better anti-cancer therapeutics, and will provide information that will allow for improved therapeutic strategies for particular tumors.

描述（改编自申请人摘要）：本研究的目的是