title: Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity.
abstract: Although several variants of DNA repair genes have been identified, their functional significance has not been determined. Using samples collected from 135 cancer-free women, this study evaluated whether amino acid substitution variants of DNA repair genes contribute to ionizing radiation (IR) susceptibility as measured by prolonged cell cycle G2 delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes: X-ray repair cross complementing group 1 (XRCC1, exon 6, C/T, 194 Arg/Trp and exon 10, G/A, 399 Arg/Gln), XRCC group 3 (XRCC3, exon 7, C/T, 241 Thr/Met) and apurinic/apyrimidinic endonuclease 1 (APE1, exon 5, T/G, 148 Asp/Glu). Fluorescence-activated cell sorter (FACS) analysis was used to measure cell cycle delay. APE1 (exon 5) genotype was significantly associated with mitotic delay (P = 0.01), with the Glu/Glu genotype having prolonged delay 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 genotypes 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 XRCC1 (exon 10) genotype (P = 0.005) in mitotic delay. Lastly, prolonged cell cycle delay was significantly associated with number of variant alleles when APE1 Asp148Glu and XRCC1 Arg399Gln genotypes were evaluated in a four-level model (chi(2) for linear trend = 10.9; P = 0.001). These results suggest that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity.
authors.affiliation: Department of Cancer Biology and Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jenhu@wfubmc.edu
authors.forename: J J
authors.initials: JJ
authors.lastname: Hu
authors.forename: T R
authors.initials: TR
authors.lastname: Smith
authors.forename: M S
authors.initials: MS
authors.lastname: Miller
authors.forename: H W
authors.initials: HW
authors.lastname: Mohrenweiser
authors.forename: A
authors.initials: A
authors.lastname: Golden
authors.forename: L D
authors.initials: LD
authors.lastname: Case
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D019757:Carbon-Oxygen Lyases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins / Q000235:genetics*; D043223:Deoxyribonuclease IV (Phage T4-Induced); D005260:Female; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011836:Radiation Tolerance / Q000235:genetics*; D012044:Regression Analysis; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; D043223:Deoxyribonuclease IV (Phage T4-Induced); D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase