Regulation of the Cell Cycle, Cell Cycle Checkpoints and Cancer

DNA damage response (DDR) pathways are triggered to ensure proper repair of DNA lesions and preserve genome integrity. Key intracellular transducers of the DNA damage are ataxia-telangiectasia mutated kinase (ATM) and ataxia-telangiectasia and Rad3-related kinase (ATR). These nuclear proteins, through dynamic interaction with chromatin-bound sensory components and phosphorylation at T/SQ residues of a multitude of substrates, including the checkpoint kinases Chk1 and Chk2, activate a network of pathways important for DNA repair, multiple cell cycle–phase arrest, transcription, and apoptosis. Interestingly, the DDR machinery is a key mediator of telomere-dependent and telomere-independent forms of cellular senescence, and provides a barrier to aberrant DNA replication induced by oncogenic stimuli. These findings and the constitutive activation of the DDR in human precancerous lesions, underscore the role of the DDR as a tumour suppressor constraining transformation by driving incipient tumour cells into apoptosis or senescence. Since genetic abnormalities of the DDR hypersensitize to genotoxic anticancer agents, this pathway represents a relevant target to increase tumour cell kill and possibly overcome drug resistance. The promising results with a number of chemical inhibitors of ATM, Chk1 and Chk2 are paving the way for new chemoradiation strategies that exploit the DDR machinery.