The integrity of our DNA is continuously threatened by both endogenous and exogenous sources of damage, which have the potential to give rise to mutations and chromosome rearrangements. Eukaryotic cells have evolved DNA Damage Response (DDR) pathways to recognize and repair such damage. The crucial role these pathways play is evidenced by the links between defects in DDR proteins and genome instability, tumorigenesis, and cancer progression. However, defects in DNA repair pathways also provide a therapeutic window that has been successfully exploited by many clinical cancer treatments, such as Topoisomerase Inhibitor (Irinotecan) for metastatic colon/rectal cancer and PARP inhibitor (Olaparib and Rubraca) for ovarian cancer.
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.
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.
