Elevated mutagenesis and decreased DNA repair at a transgene are associated with proliferation but not apoptosis in p53-deficient cells.
p53, the most commonly mutated gene in human tumors, is believed to play a crucial role in the prevention of cancer by protecting cells from mutation, a theory commonly known as the "Guardian of the Genome" hypothesis. There are two hypotheses as to how this can occur. In the first, p53 protects the genome by retarding the cell cycle, thus allowing more time for DNA repair. In the second, p53 reduces cancer by initiating apoptosis in damaged cells, thus making it impossible for these cells to become carcinogenic. This study directly tested these two theories in primary murine embryonic fibroblasts on a common genetic background with and without p53, using a lacI transgene as a mutational target. The data demonstrate that, as a direct consequence of cell cycle delay, p53 slowed the induction of mutations and decreased their frequency but had little effect on the frequency of apoptosis. This indicates that the function of p53 in cell cycle control is more important than the role of p53 in apoptosis, for mutation prevention, in any uniform cell population. Moreover, p53-mediated protection is further improved in slowly dividing cells, suggesting that p53 may be particularly important in protecting stem cells from mutation. The role of apoptosis in vivo, however, may be to remove whole tissue subpopulations that can be renewed by less sensitive stem cells.
Bielas
Jason H
JH
Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.
Heddle
John A
JA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D003433:Crosses, Genetic; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D016158:Genes, p53; D005838:Genotype; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology*; D009153:Mutagens; D011247:Pregnancy; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics*
D017931:DNA Primers; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D005038:Ethylnitrosourea