Cell cycle arrest defect in Li – Fraumeni Syndrome: a mechanism of cancer predisposition?

Abstract

Cancer predisposition in approximately 60% of Li – Fraumeni Syndrome (LFS) families is associated with germline mutation of the TP53 gene. The p53 protein has been shown to mediate G₁ arrest following DNA damage. We have investigated γ-irradiation-induced transient and permanent G₁ arrest in normal and LFS fibroblasts. The duration of transient G₁ arrest varied between strains, but there was no difference in the range between normal (2 – 12 h) and LFS (1 – 13 h) cells. However, the extent of permanent G₁ arrest was greatly reduced in LFS fibroblasts (mean 33±8% of the cell population) compared with normals (mean 67±9%) and correlated with their increased radiation survival (r=0.97, P<0.001). This phenotype was observed in LFS fibroblasts both with (seven cases) and without (two cases) TP53 mutation. Parallel studies with fibroblasts derived from cancer-prone, p53-deficient mice revealed no radiation-induced G₁ cell cycle arrest in p53 null (−/−) cells. The p53 +/− cells were comparable to the wt p53 cells in transient G₁ arrest capacity, but showed a diminished permanent G₁ arrest. These data clearly implicate p53 function in permanent G₁ arrest. The reduced capacity for DNA damage-induced, permanent G₁ arrest in LFS may contribute significantly to cancer predisposition in this familial syndrome.