ABSENCE OF P53 PERMITS PROPAGATION OF MUTANT-CELLS FOLLOWING GENOTOXIC DAMAGE

Much evidence has been gathered in support of a critical role for p53 in the cellular response to DNA damage. p53 dysfunction is associated with progression and poor prognosis of many human cancers and with a h igh incidence of tumours in p53 knockout mice. The absence of a p53-de pendent G(1) arrest that facilitates DNA repair or apoptosis might imp act critically on clinical cancer in two ways. First, by abrogating th e impact on therapy that operates via genotoxic damage and apoptosis; and second, by encouraging progression either by inducing genomic inst ability and DNA mis-repair or by permitting survival of mutants. Howev er, experiments examining the relationship between p53 deficiency and mutation frequency have so far failed to confirm these predictions. Th e precise role played by p53 is therefore unclear. We now report use o f a short term in vitro approach to assess the influence of p53 on rad iation-induced mutations at the hprt locus in murine B cell precursors that are normally radiation ultrasensitive, We find a high number of hprt mutants among X-irradiated p53 null cells, which results from pre ferential survival as clonogenic mutants rather than from a p53-depend ent increase in mutation rate. This result has important implications for genotoxic cancer therapy.