Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity

Although several variants of DNA repair genes have been identified, their f unctional significance has not been determined. Using samples collected fro m 135 cancer-free women, this study evaluated whether amino acid substituti on variants of DNA repair genes contribute to ionizing radiation (IR) susce ptibility as measured by prolonged cell cycle Gz delay. PCR-restriction fra gment length polymorphism (RFLP) assays were used to determine four genotyp es: X-ray repair cross complementing group 1 (XRCC1, exon 6, C/T, 194 Arg/T rp and exon 10, G/A, 399 Arg/Gln), XRCC group 3 (XRCC3, exon 7, C/T, 241 Th r/Met) and apurinic/apyrimidinic endonuclease 1 (APE1, exon 5, T/G, 148 Asp /Glu), Fluorescence-activated cell sorter (FACS) analysis was used to measu re cell cycle delay, APE1 (exon 5) genotype was significantly associated wi th mitotic delay (P = 0.01), with the Glu/Glu genotype having prolonged del ay compared with the other two genotypes. The mitotic delay index (mean +/- SD) in women with the APE1 codon 148 Asp/Asp, Asp/Glu and Glu/Glu genotype s was 30.95 +/- 10.15 (n = 49), 30.65 +/- 10.4 (n = 60) and 39.56 +/- 13.12 (n = 21), respectively, There was a significant interaction between family history (FH) and APE1 (exon 5) genotype (P = 0.007) as well as FH and XRCC 1 (exon 10) genotype (P = 0.005) in mitotic delay, Lastly, prolonged cell c ycle delay was significantly associated with number of variant alleles when APE1 Asp148Glu and XRCC1 Arg399Gln genotypes were evaluated in a four-leve l model (chi (2) for linear trend 10.9; P = 0.001), These results suggest t hat amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity.