DNA-PK-DNA complexes: the molecular mechanism triggering differentiated DNA Damage Repair signaling pathways

学生战略优先领域：基础生物科学支撑疾病摘要：DNA双链断裂(DSB)是一种毒性损伤，其错误修复最终导致缺失和染色体易位。此外，DNA损伤修复蛋白在肿瘤学中被认为是药物靶点。生物进化来处理DSB的两种最重要的修复机制是同源重组(HR)和非同源末端连接(NHEJ)。在这些途径之间的选择是至关重要的，但它仍然是DSB修复的一个鲜为人知的方面。在本项目中，我们旨在通过用Cryo-EM解算DNAPK：DDR调节剂络合物的结构来研究这一过程背后的分子机制。该结构将使我们能够设计一个不能与DNAPK结合的突变调节剂，并最终探索功能突变缺失的细胞效应，从而剖析其在途径选择中的作用。

Studentship strategic priority area:Basic Bioscience Underpinning HeathAbstract: DNA Double stranded Breaks (DSBs) are toxic lesions and their misrepair culminates in deletions and chromosomal translocations. Moreover, DNA Damage Repair proteins are reputed drug targets in oncology. The two most prominent repair mechanisms that organisms evolved to deal with DSBs are homologous recombination (HR) and non-homologous end-joining (NHEJ). The choice between these pathways is critical, but it remains a poorly understood aspect of DSB repair. In this project we aim to investigate the molecular mechanism underlying this process by solving the structure of DNAPK:DDR modulator complexes by Cryo-EM. The structure will permit us to devise a mutant modulator unable to bind DNAPK and finally probe the cellular effects of the loss of function mutant, thus dissecting its role in pathway choice.