LOSS OF HETEROZYGOSITY INDUCED BY A CHROMOSOMAL DOUBLE-STRAND BREAK

The repair of chromosomal double-strand breaks (DSBs) is necessary for genomic integrity in all organisms, Genetic consequences of misrepair include chromosomal loss, deletion, and duplication resulting in loss of heterozygosity (LOH), a common finding in human solid tumors. Alth ough work with radiation-sensitive cell lines suggests that mammalian cells primarily rejoin DSBs by nonhomologous mechanisms, alternative m echanisms that are implicated in chromosomal LOH, such as allelic reco mbination, may also occur, We have examined chromosomal DSB repair bet ween homologs in a gene targeted mammalian cell line at the retinoblas toma (Rb) locus. We have found that allelic recombinational repair occ urs in mammalian cells and is increased at least two orders of magnitu de by the induction of a chromosomal DSB. One consequence of allelic r ecombination is LOH at the Rb locus, Some of the repair events also re sulted in other types of genetic instability, including deletions and duplications. We speculate that mammalian cells may have developed eff icient nonhomologous DSB repair processes to bypass allelic recombinat ion and the potential for reduction to homozygosity.