One of the most dangerous DNA lesions is a DNA Double Strand Break (DSB), in which the backbones of the duplex DNA strands are simultaneously broken. Unrepaired DSBs threaten cell survival by altering transcription, replication, and chromosome segregation. Moreover, the inappropriate repair of multiple DSBs can result in chromosome translocations, a key step in the initial stages of tumorigenesis. Using various cellular systems to generate proximal and distal DSBs, we recently showed that increased chromatin mobility promotes the mis-repair of multiple distal DSBs, revealing the fundamental importance of controlled chromatin dynamics to accurate DNA repair.
We are combining mouse genetics and quantitative time-lapse imaging to dissect the principles of chromatin dynamics and understand its contribution to DNA repair, tumorigenesis and ageing. We also aim to investigate the mechanisms that regulate mobility, identify new molecular factors involved in regulating chromatin dynamics, and to evaluate the consequences of altered mobility on genome integrity in both normal and cancer cells.