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

Studentship strategic priority area:Basic Bioscience Underpinning Heath

Abstract:

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.