Linking Structure and Function for the DNA Repair Complex Mre11-Rad50-Nbs1

__Abstract__ Repair of DNA damage is an essential process in all cells and an important mechanism to avoid cancer development in animals. The repair of DNA double strand breaks (DSB) requires many component proteins including the Mre11-Rad50-Nbs1 (MRN) complex that serves different functions in this process. This thesis explores how the organization of the MRN components in the complex contributes to and controls functions such as DNA binding and DNA tethering. Changes in the structure of the complex upon DNA binding are likely responsible for its role in DNA tethering and damage signaling. The first chapter reviews the homologous recombination (HR) and non-homologous end joining (NHEJ) pathway of DSB repair and the known roles of Mre11, Rad50 and Nbs1. The conformational changes induced by ATP binding as well as some standing questions regarding the dynamics and stoichiometry of this protein complex are discussed. The experimental work described in the rest of the thesis us