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.

Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy

“…These results are in accord with our findings that the wild-type genotypes of both XPD and XRCC1 are associated with shorter cancer-specific survival in muscle-invasive bladder cancer patients treated with CRT. However, the results of Hu et al (2001) seem to contradict those of Sak et al (2005) noted above. Sak et al (2005) stated that one possible explanation is that the reduced expression of XRCC1 and APE1 merely reflects the poorly differentiated nature of tumour cells in more aggressive tumours, and that cells from aggressive tumours with extensive genomic instability could contain chromosomal aberrations that result in the failure of transcription of genes, including DNA repair genes, thus resulting in lower protein expression of the gene products.…”

“…Ionising radiation exposure damages cellular DNA in many ways, requiring the concerted action of a number of DNA repair enzymes to restore genomic integrity (Hu et al, 2001). The BER and HRR pathways are particularly important with regard to this (Thompson and West, 2000;Khanna and Jackson, 2001).…”

“…Yoon et al (2005) showed that the variant-type XRCC1 Arg399Gln genotype is associated with progression-free survival advantage in non -small-cell lung cancer patients who have received radiotherapy. Moreover, Hu et al (2001) indicated that amino-acid substitution variants of XRCC1 and APE1 might contribute to ionising radiation hypersensitivity. These results are in accord with our findings that the wild-type genotypes of both XPD and XRCC1 are associated with shorter cancer-specific survival in muscle-invasive bladder cancer patients treated with CRT.…”

“…Moreover, DNA damaged by ionising radiation is repaired mainly by the BER pathway and by homologous recombination repair (HRR) and nonhomologous end-joining repair, which are types of DSB repair (Hu et al, 2001;Khanna and Jackson, 2001). Modulation of repair capacity by the SNPs in DNA repair genes might therefore affect response and prognosis following platinumbased chemoradiotherapy (CRT) for cancer.…”

A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer

“…The 399Arg>Gln is situated within the BRCT-1 region harboring the poly(ADP-ribose)polymerase-binding domain (Shen et al, 1998). A few previous studies reported that the 399Gln allele was associated with a higher level of DNA adducts and glycophorin A mutations (Lunn et al, 1999;Matullo et al, 2001a, b), increased sister chromatin exchange frequencies (Duell et al, 2000), or higher sensitivity to ionizing radiation and chemical mutagens (Hu et al, 2001;Wang et al, 2003a, b). However, conflicting results also exist, showing no association between the 399Arg>Gln polymorphism and DNA adduct levels (Matullo et al, 2001a, b;Palli et al, 2001).…”