Radiation-induced genetic instability in vivo depends on p53 status.
In response to ionizing radiation and other agents that damage DNA, the p53 tumor suppressor protein activates multiple cellular processes including cell cycle checkpoints and programmed cell death. Although loss of p53 function is associated with radiation-induced genetic instability in cell lines, it is not clear if this relationship exists in vivo. To study the role of p53 in maintenance of genetic stability in normal tissues following irradiation, we have measured mutant frequencies at the adenine phosphoribosyltransferase (Aprt) and hypothanine-guanine phosphoribosyltransferase (Hprt) loci and examined mechanisms of loss of heterozygosity (LOH) in normal T cells of p53-deficient, Aprt heterozygous mice that were subjected to whole-body irradiation with a single dose of 4Gy X-rays. The radiation-induced mutant frequency at both the Aprt and Hprt loci was elevated in cells from mice with different p53 genotypes. The radiation-induced elevation of p53-/- mice was significantly greater than that of p53+/- or p53+/+ mice and was caused by several different kinds of mutational events at the both chromosomal and intragenic levels. Most significantly, interstitial deletion, which occurs rarely in unirradiated mice, became the most common mechanism leading to LOH in irradiated p53 null mice. These observations support the idea that absence or reduction of p53 expression enhances radiation-induced tumorigenesis by increasing genetic instability at various loci, such as those for tumor suppressor genes.
Liang
Li
L
Department of Genetics, State University of New Jersey, Rutgers, Piscataway, NJ 08854, USA.
Shao
Changshun
C
Deng
Li
L
Mendonca
Marc S
MS
Stambrook
Peter J
PJ
Tischfield
Jay A
JA
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D017931:DNA Primers; D005260:Female; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008938:Mitosis / Q000235:genetics; D009153:Mutagens / Q000494:pharmacology; D011995:Recombination, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014965:X-Rays
D017931:DNA Primers; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D004247:DNA