Absence of p53 permits propagation of mutant cells following genotoxic damage

Abstract

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 high incidence of tumours in p53 knockout mice. The absence of a p53-dependent G 1 arrest that facilitates DNA repair or apoptosis might impact critically on clinical cancer in two ways. First, by abrogating the impact on therapy that operates via genotoxic damage and apoptosis; and second, by encouraging progression either by inducing genomic instability and DNA mis-repair or by permitting survival of mutants. However, experiments examining the relationship between p53 de®ciency and mutation frequency have so far failed to con®rm these predictions. The precise role played by p53 is therefore unclear. We now report use of a short term in vitro approach to assess the in¯uence of p53 on radiation-induced mutations at the hprt locus in murine B cell precursors that are normally radiation ultrasensitive. We ®nd a high number of hprt mutants among X-irradiated p53 null cells, which results from preferential survival as clonogenic mutants rather than from a p53-dependent increase in mutation rate. This result has important implications for genotoxic cancer therapy.

The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid

“…Hence, our results indicate that p53 can play the role of guardian of the genome for point mutations, at least for certain kinds of DNA damage. The e cacy of p53-dependent MFR may also depend on the level of DNA damage as well as on the cell type (Gri ths et al, 1997). The kinds of DNA damage subjected to p53-dependent MFR remain to be determined.…”

“…It has been reported that p53 has no e ect on spontaneous lacI mutation frequencies in wild type and p53-negative transgenic mice (Nishino et al, 1995), on spontaneous and 4-nitroquinoline-1-oxide-induced lacI mutations in wild type and p53-de®cient mouse embryonic ®broblasts (Sands et al, 1995), on spontaneous hprt mutations in p53-inducible human osteosarcoma cells (Yamagishi et al, 1997b), or on ultraviolet (UV)-induced supF mutations in a shuttle vector in wild type and p53-de®cient mouse embryonic ®broblasts (Ishizaki et al, 1996). Furthermore, there is no X-ray-induced hypermutability of the hprt gene in B cell precursors from p53 7 /p53 7 mice (Gri ths et al, 1997). On the other hand, p53 was reported to reduce UV-induced hprt mutations in human osteosarcoma cells (Yamagishi et al, 1997b;Yagi et al, 1998) and in a supF target gene in an integrated l genome and in a shuttle vector (Yamagishi et al, 1997b).…”

Radioresistant MTp53-expressing rat embryo cell transformants exhibit increased DNA-dsb rejoining during exposure to ionizing radiation

“…Alternate mechansims for radioresistance could involve a higher level of baseline DNA repair and survival of mutant cells following the loss of genomic stability a orded by the WTp53 protein (Gri ths et al, 1997;Morgan and Murnane, 1995). Of note, inactivation of WTp53 function can result in high rates of homologous recombination and a trend towards increased non-homologous recombination (the latter thought to be a more important pathway for DNA-dsb repair in mammalian cells; Kanaar and Hoeijmakers, 1997;Mekeel et al, 1997).…”

An Eμ-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

“…This outcome can however be compromised if key regulatory proteins are dysfunctional. Lack of p53 (Clarke et al, 1993;Gri ths et al, 1997) or overexpression of BCL-2 protein (Gri ths et al, 1994a;Merino et al, 1994;Vaux et al, 1988) can, for example, rescue lymphoid cells otherwise destined for destruction following low level exposure to genotoxic chemicals, ionizing irradiation or corticosteroids. The acquisition of such blocks to cell death can have important consequences to both leukaemogenesis, response to genotoxic therapy and further malignant progression.…”

“…The acquisition of such blocks to cell death can have important consequences to both leukaemogenesis, response to genotoxic therapy and further malignant progression. Animals that are homozygous null for p53 are at high risk of developing leukaemia/lymphoma (Donehower et al, 1992;Purdie et al, 1994) and exposure of p53 null lymphocytes in vitro to Xirradiation results in survival of clonogenic mutants that would have died if in a wild-type, p53 competent background (Gri ths et al, 1997). These observations suggest that the availability of apoptotic pathways in cells can make a very signi®cant impact on the balance of transformation and cell death outcomes for genotoxic exposures.…”