DNA damage responses in mammalian cells and their contribution to human health disorders

DNA damage responses encompass DNA repair processes and signal transduction mechanisms. The grant focuses on the response to DNA double strand breaks (DSBs), an important lethal and carcinogenic lesion. DSBs arise from endogenous oxidative damage, during certain metabolic processes including V(D)J recombination, a step during immune development, and following exposure to ionising radiation. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent DSB repair pathways and Ataxia telangiectasia mutated (ATM) regulates the major DSB signalling response. This programme aims to understand how DSBs are processed and rejoined by NHEJ and its contribution to human disease. Three disorders conferred by defects in NHEJ have known and all are associated with immunodeficiency and radiosensitivity. ATM signalling is dispensable for most DSB repair. However, a subset of DSBs require ATM signalling proteins and a nuclease, Artemis. We will examine the roles of Artemis and ATM in DSB repair. ATR regulates a related signalling process that is activated by stalled replication forks and bulky lesions. Seckel Syndrome is characterised by defects in the ATR signalling pathway, although not all defective genes have been identified. This programme will also aim to gain insight into ATR signalling and its contribution to disorders affecting human health.

DNA damage responses encompass DNA repair processes and signalling transduction mechanisms. DNA non-homologous end-joining (NHEJ) is the major process that repairs DNA double strand breaks (DSBs) induced by ionising radiation. Recent studies have shown that the ATM-dependent signal transduction pathway also impacts upon DNA repair by activating mechanisms required for DNA end-processing and cell cycle checkpoint arrest. NHEJ is required for efficient V(D)J recombination and also functions during development. One aim of this programme is to gain insight into how DSBs are processed and rejoined by NHEJ and the contribution of NHEJ to human health disorders. ATR regulates a related signal transduction process that is activated by stalled replication forks and bulky lesions. We have shown that Seckel Syndrome is characterised by defects in the ATR signalling pathway. This programme will also aim to gain insight into ATR signalling and its contribtuion to disorders affecting human health.