Essential roles for Pol delta in Pol theta mediated end joining

项目总结(部分来自原提案的总体具体目标) 聚合酶theta(POLθ，基因名POLQ)在BRCA1/2基因缺陷的癌症中是必不可少的--或者实际上在细胞中 在参与DNA损伤反应的140个不同基因中，任何一个都有缺陷--但它的缺陷是好的 在大多数正常细胞中是耐受的。因此，靶向抑制POLθ可能在许多 20%的人类癌症。 到目前为止，对于这种290 kDa的多结构域和多活性的酶是如何作用的还不清楚。 它的生物学作用，以及个体通路步骤是如何执行的。我们正在解决这一知识鸿沟 目标1：Polδ的角色调查正在执行路径步骤，我们在此帮助下启动这些步骤 要实现这一目标，补充是必不可少的。我们还在调查参与的蜂窝环境 POLθ或TMEJ在目标2中；3寻求整合从为支持总体目标而开展的工作中获得的见解1 2开发更安全、更有效的治疗方法的理论基础。

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.