Perturbations to the normal apoptotic response would be predicted to impact upon longer term survival as determined through the microcolony assay. I therefore examine clonogenic survival using this approach in Msh2, Mlh-1 and p53 null mice. Despite being necessary for apoptosis for all cytotoxic agents studied, loss of p53 only led to an increased in survival following cisplatin treatment and not following NMNU or Nitrogen Mustard treatment. Similar dissociation between apoptosis and clonogenic survival was observed in the Mlh-1 null mice, which showed increased clonogenic survival despite possessing an intact apoptotic response. I also investigate the interaction between Msh2 and p53 in tumourigenesis. Both homozygosity for p53 were found to dramatically accelerate tumourigenesis on a mismatch (Msh-2) deficient background. Significantly, the levels of microsatellite instability were highest in tumours which were additionally heterozygous for p53. EMSA, Western and immunohistochemistry analysis of these tumours indicated retention of p53 function in at least a proportion of these tumours. Similar data were obtained from primary cultures, with again increased microsatellite instability and retained p53 functionality in cultures derived from p53 heterozygotes. Taken together, this data shows that hemizygosity for p53 increases microsatellite instability and that, at least in percentage of tumours, complete loss of p53 is not a required event. These findings have particular relevance to our understanding of cross talk between p53 and MMR deficiency in human colorectal disease. Finally, I applied the battery of analyses used throughout this thesis to a new candidate tumour suppressor, Mbd4. Mbd4 deficient mice have no overt phenotype, but fail to mediate normal apoptosis following a wide variety of DNA damage. Following cisplatin treatment, Mbd4 treatment confers increased clonogenic survival Surprisingly, Mbd4 mice are not characterised by an increase in either spontaneous or induced mutation rate, but when crossed to Apc^Min mice they accelerate tumour development. These studies demonstrate spontaneous or induced mutation rate, but when cross to Apc^Min mice they accelerate tumour development. These studies demonstrate that Mbd4 is a central mediator of the response to DNA damage and that it functions as an intestinal tumour suppressor in the mouse.