CECAD Microsite

DNA Damage

Following DNA damage, cells activate distinct signaling networks mediating cell cycle checkpoints, DNA repair, and apoptosis. These networks are highly interconnected through complex nonlinear relationships, but how they function together at the systems level is poorly understood. Immediately following the encounter of genotoxic lesions, the proximal DNA damage response (DDR) kinases ATM and ATR are activated. In a signal amplification step, these proximal DDR kinases subsequently phosphorylate and activate numerous downstream effector kinases, including CHK1, CHK2 and MK2. Together this kinase signaling network imposes a cell cycle arrest through mediating inhibitory phosphorylations on CDC25 family member, which ultimately prevents activation of CDKs, the essential drivers of the eukaryotic cell cycle. In addition, signaling through this checkpoint kinase network also induces apoptosis through the activation of p53 and its downstream target genes. Lastly, DDR kinase signaling is involved in numerous DNA repair pathways, including homologous recombination, non-homologous end joining, nucleotide excision repair and others. Given their role in genome maintenance, it is perhaps not surprising that components of the DDR network are among the most commonly mutated genes in human malignancies.  It is thought that these DDR defects contribute to oncogenesis by promoting a ‘mutator-phenotype’ allowing the acquisition of additional genetic lesions driving transformation.

Our lab has a long-standing interest in understanding the molecular nuts and bolts of the DDR. We have recently developed a series of novel Atm, Cdkn1a and Bbc3 alleles, which we are using to unravel the signaling cues that mediate the cellular decision between cell cycle arrest and apoptosis.