Open AccessJournal Article
Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.
Shen Mr,Jones Im,Mohrenweiser H +2 more
TL;DR: Estimation of the extent of DNA sequence variation among individuals in genes encoding proteins of the DNA repair pathways finds nine different amino acid substitution variants have been identified in resequencing of the exons of three nucleotide excision repair genes, a gene involved in double-strand break repair/recombination genes, and a gene functioning in base excision Repair and the repair of radiation-induced damage.
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Abstract: The removal or repair of DNA damage has a key role in protecting the genome of the cell from the insults of cancer-causing agents. This was originally demonstrated in individuals with the rare genetic disease xeroderma pigmentosum, the paradigm of cancer genes, and subsequently in the relationship between mismatch repair and colon cancer. Recent reports suggest that individuals with less dramatic reductions in the capacity to repair DNA damage are observed at polymorphic frequency in the population; these individuals have an increased susceptibility to breast, lung, and skin cancer. We report initial results from a study to estimate the extent of DNA sequence variation among individuals in genes encoding proteins of the DNA repair pathways. Nine different amino acid substitution variants have been identified in resequencing of the exons of three nucleotide excision repair genes (ERCC1, XPD, and XPF), a gene involved in double-strand break repair/recombination genes (XRCC3), and a gene functioning in base excision repair and the repair of radiation-induced damage (XRCC1). The frequencies for the nine different variant alleles range from 0.04 to 0.45 in a group of 12 healthy individuals; the average allele frequency is 0.17. The potential that this variation, and especially the six nonconservative amino acid substitutions occurring at residues that are identical in human and mouse, may cause reductions in DNA repair capacity or the fidelity of DNA repair is intriguing; the role of the variants as cancer risk factors or susceptibility alleles remains to be addressed.
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Citations
Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells
Eric J. Duell,John K. Wiencke,Tsun-Jen Cheng,Andrea Varkonyi,Zheng Fa Zuo,Tara Devi S. Ashok,Eugene J. Mark,John C. Wain,David C. Christiani,Karl T. Kelsey +9 more
TL;DR: The results suggest that carriers of the polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age-related DNA damage.
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 +5 more
TL;DR: It is suggested that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity as measured by prolonged cell cycle G2 delay.
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Identification of Variants of CYP3A4 and Characterization of Their Abilities to Metabolize Testosterone and Chlorpyrifos
Diana Dai,Jun Tang,Randy L. Rose,Ernest Hodgson,Rachelle J. Bienstock,Harvey W. Mohrenweiser,Joyce A. Goldstein +6 more
TL;DR: Single nucleotide polymorphisms in CYP3A4 were identified by direct sequencing of genomic DNA in 72 individuals from three different ethnic groups, including Caucasians, Blacks (African-Americans and African pygmies), and Asians, and racial variability was observed for the frequency of individual SNPs.
366
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Genetic Susceptibility to Lung Cancer The Role of DNA Damage and Repair
TL;DR: Lung cancer epitomizes the concept that heritable traits modify the effects of environmental exposures, and more than 80% of lung cancers are attributed to tobacco
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