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 high incidence of tumours in p53 knockout mice. The absence of a p53-dependent G1 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 deficiency and mutation frequency have so far failed to confirm 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 influence of p53 on radiation-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 preferential survival as clonogenic mutants rather than from a p53-dependent increase in mutation rate. This result has important implications for genotoxic cancer therapy.
Griffiths
S D
SD
Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK.
Clarke
A R
AR
Healy
L E
LE
Ross
G
G
Ford
A M
AM
Hooper
M L
ML
Wyllie
A H
AH
Greaves
M
M
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004307:Dose-Response Relationship, Radiation; D016158:Genes, p53; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016296:Mutagenesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D014965:X-Rays
D015851:Interleukin-7; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D007041:Hypoxanthine Phosphoribosyltransferase