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

Jennifer J. Hu, Tasha R. Smith, Mark Steven Miller, Harvey W. Mohrenweiser, Andrea Golden, L. Douglas Case

Research output: Contribution to journalArticlepeer-review

290 Scopus citations

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 (X2 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.

Original languageEnglish (US)
Pages (from-to)917-922
Number of pages6
JournalCarcinogenesis
Volume22
Issue number6
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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