RecombInsight: Discovery in Mammalian Homologous Recombination DNA Repair

同源重组DNA修复（Homomorphination DNA repair，HR）是双链DNA断裂修复的最精确形式。促进它的几个基因的突变与人类综合征有关，包括早发性衰老和癌症易感性。靶向HR缺陷是几种抗癌治疗的核心，而诱导毒性HR中间体是新兴治疗策略的基础。HR分为两个阶段。第一种方法涉及修剪其中一条断裂的DNA链，这一点已经很好理解。然而，接下来的步骤是机械知识的差距，阻碍了对癌症易感综合征和新疗法发展的理解。该项目旨在发现哺乳动物细胞中研究较少的HR第二阶段的分子细节。为了实现这一目标，它将确定支持这一过程的新细胞因子，并开发新的方法来评估每一步发生的核酸和蛋白质事件。该项目将利用化学、改进的基因组编辑、创新的染色体构象和成像技术的概念来实现这一步的变化。

Homologous Recombination DNA repair (HR) is the most accurate form of double-strand DNA break repair. Mutations in several genes that promote it are associated with human syndromes, including early-onset ageing and cancer predisposition. Targeting HR deficiency is at the core of several anti-cancer treatments while inducing toxic HR intermediates underpins an emerging therapeutic strategy. HR happens in two phases. The first involves trimming one of the broken DNA strands and is well understood. However, the next steps are mechanistic knowledge gaps, holding back understanding of cancer predisposition syndromes and new therapy developments.This project aims to discover the molecular details of this less-studied second phase of HR in mammalian cells. To achieve this it will identify new cellular factors that support the process and develop new means to assess the nucleic acid and protein events that occur at each step. The project will exploit concepts from chemistry, improved genome editing, innovative chromosome conformation and imaging technologies to deliver this step-change.