A novel role for the Bcl‐2 protein family: specific suppression of the RAD51 recombination pathway

The oncogenic role of Bcl‐2 is generally attributed to its protective effect against apoptosis. Here, we show a novel role for Bcl‐2: the specific inhibition of the conservative RAD51 recombination pathway. Bcl‐2 or Bcl‐ X L overexpression inhibits UV‐C‐, γ‐ray‐ or mutant p53‐induced homologous recombination (HR). Moreover, Bcl‐2 recombination inhibition is independent of the role of p53 in G 1 arrest. At an acute double‐strand break in the recombination substrate, Bcl‐2 specifically inhibits RAD51 ‐dependent gene conversion without affecting non‐conservative recombination. Bcl‐2 consistently thwarts recombination stimulated by RAD51 overexpression and alters Rad51 protein by post‐translation modification. Moreover, a mutant G145A Bcl‐2, which is defective in Bax interaction and in apoptosis repression, also inhibits recombination, showing that the death and recombination repression functions of Bcl‐2 are separable. Inhibition of error‐free repair pathways by Bcl‐2 results in elevated frequencies of mutagenesis. The Bcl‐2 gene therefore combines two separable cancer‐prone phenotypes: apoptosis repression and a genetic instability/mutator phenotype. This dual phenotype could represent a mammalian version of the bacterial SOS repair system.