Essential roles for Pol delta in Pol theta mediated end joining

Pol delta 在 Pol theta 介导的末端连接中的重要作用

• 批准号: 10595374
• 负责人: DALE A RAMSDEN
• 金额: $ 4.95万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595374
• 关键词: Address; Biological; Cells; Chromosomal Breaks; DNA Damage; Data; Genes; Goals; Human; Individual; Investigation; Knowledge; Malignant Neoplasms; Mediating; Names; Normal Cell; Pathway interactions; Polymerase; Role; Work; brca gene; effective therapy; enzyme activity; insight; programs; reconstitution; repaired; response

Project summary (partly from overall specific aims of original proposal) Polymerase theta (Pol θ, gene name Polq) is essential in cancers deficient in BRCA1/2 – or indeed in cells deficient in any one of 140 different genes involved in DNA damage responses – yet its deficiency is well tolerated in most normal cells. As a consequence, targeted inhibition of Pol θ could be effective in as many of 20% of human cancers. To date, much remains unclear as to how this 290 kDa multi-domain and multi-activity enzyme contributes to its biological role, and how individual pathway steps are performed. We are addressing this knowledge gap in Aim 1; investigation of roles for Pol δ is performing pathways steps, which we initiate with the help of this supplement is essential to achieve this goal. We are additionally investigating the cellular contexts that engage Pol θ or TMEJ in Aim 2; 3 seeks to integrate insights gained from work performed in support of overall Aims 1 and 2 to develop rationales for safer, more effective therapies.

项目摘要（部分来自原始提案的总体具体目标） 聚合酶 theta（Pol θ，基因名称 Polq）对于缺乏 BRCA1/2 的癌症（甚至在细胞中）至关重要 参与 DNA 损伤反应的 140 个不同基因中的任何一个都存在缺陷——但它的缺陷是很好的 大多数正常细胞都可以耐受。因此，有针对性地抑制 Pol θ 可能在许多方面都有效。 20%的人类癌症。 迄今为止，关于这种 290 kDa 多结构域和多活性酶如何促进 它的生物学作用，以及各个途径步骤如何执行。我们正在解决这一知识差距 目标1；对 Pol δ 的作用的研究正在执行路径步骤，我们在此帮助下启动 补充对于实现这一目标至关重要。我们还在研究参与的细胞环境 目标 2 中的 Pol θ 或 TMEJ； 3 力求整合从支持总体目标 1 的工作中获得的见解 2 阐述更安全、更有效的治疗方法的基本原理。