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 effec t against apoptosis, Here, we show a novel role for Bcl-2: the specific inh ibition of the conservative RAB51 recombination pathway. Bcl-2 or Bcl-X-L o verexpression inhibits UV-C-, gamma -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 c onversion without affecting non-conservative recombination. Bcl-2 consisten tly thwarts recombination stimulated by RAD51 overexpression and alters Rad 51 protein by post-translation modification, Moreover, a mutant (G145A)Bcl- 2, which is defective in pax 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 th erefore combines two separable cancer-prone phenotypes: apoptosis repressio n and a genetic instability/mutator phenotype, This dual phenotype could re present a mammalian version of the bacterial SOS repair system.