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Gene Conversion Is Strongly Induced in Human Cells by Double-strand Breaks and Is Modulated by the Expression of BCL-x_L¹

Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 [C. W., S. S. G., A. K.], and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [A. J. P., M. J.]

Homology-directed repair (HDR) of DNA double-strand breaks (DSBs) contributes to the maintenance of genomic stability in rodent cells, and it has been assumed that HDR is of similar importance in DSB repair in human cells. However, some outcomes of homologous recombination can be deleterious, suggesting that factors exist to regulate HDR. We demonstrated previously that overexpression of BCL-2 or BCL-x_L enhanced the frequency of X-ray-induced TK1 mutations, including loss of heterozygosity events presumed to arise by mitotic recombination. The present study was designed to test whether HDR is a prominent DSB repair pathway in human cells and to determine whether ectopic expression of BCL-x_L affects HDR. Using TK6-neo cells, we find that a single DSB in an integrated HDR reporter stimulates gene conversion 40–50-fold, demonstrating efficient DSB repair by gene conversion in human cells. Significantly, DSB-induced gene conversion events are 3–4-fold more frequent in TK6 cells that stably overexpress the antiapoptotic protein BCL-X_L. Thus, HDR plays an important role in maintaining genomic integrity in human cells, and ectopic expression of BCL-x_L enhances HDR of DSBs. This is the first study to highlight a function for BCL-x_L in modulating DSB repair in human cells.

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