High frequency of deletions at the hypoxanthine-guanine phosphoribosyltransferase locus in an ataxia-telangiectasia lymphoblastoid cell line irradiated with gamma-rays.

The molecular nature of gamma-ray-induced mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in an ataxia-telangiectasia (A-T) lymphoblastoid cell line was investigated. Twelve of 15 gamma-ray-induced HPRT-deficient mutants showed deletions. Eight of them had lost the entire HPRT gene, one showed a 1.9-kb deletion, and three had deletions of about 40-150 base pairs. Of the eight mutants that lost the entire gene, five had also lost both DXS79 and DXS86, flanking markers of the HPRT locus. The spectrum of mutations induced by gamma-irradiation in the A-T cells showed a high frequency of deletions in comparison with that in a control cell line, WIL2-NS. Sequence analysis of breakpoint junctions in four mutants revealed that three of them had junctions between short identical sequences at each breakpoint, leaving one copy at the junction. These results suggest that non-homologous end-joining is the major mechanism for deletion formation in A-T cells.