Alpha particle mutagenesis of human lymphoblastoid cell lines

Despite being derived from the same donor, the human lymphoblastoid cell lines WTK1 and TK6 have markedly different responses to low LET radiation. We originally observed that WTK1 was more resistant to the cytotoxic effects of X-irradiation, but significantly more sensitive to mutation induction at both the TK and HPRT loci. In an effort to better understand these properties, we have examined the effects of alpha-particles on these cells. Relative to TK6, WTK1 has enhanced survival and mutation after both X-ray and alpha-particle exposure. While the HPRT locus was significantly more mutable in WTK1 as a function of alpha-particle versus X-ray dose, the TK locus was only slightly more sensitive to alpha-particle mutagenesis. In addition, the slowly growing TK mutants that constitute the majority of X-ray-induced TK mutants of TK6 were recovered in lower proportions following alpha-particle exposures. This is consistent with the further finding that in both cell lines, loss of heterozygosity occurred in a smaller fraction of alpha-induced TK mutants than X-ray-induced mutants. These results are consistent with our previous model suggesting that WTK1 has an error-prone repair pathway that is either missing or deficient in TK6, and further suggest that this pathway may be involved in the processing of alpha-particle-induced damage.