title: The influence of XPD, APE1, XRCC1, and NBS1 polymorphic variants on DNA repair in cells exposed to X-rays.
abstract: Polymorphism of genes coding for proteins which participate in DNA repair may predispose to or protect against development of cancer. Here we studied how common polymorphisms of the genes XPD (Asp312Asn and Lys751Gln), APE1 (Asp148Glu), XRCC1 (Arg399Gln), and NBS1 (Gln185Glu) influence DNA repair and other responses after X-irradiation of lymphocytes from colon carcinoma patients. Genotypes with polymorphic Asp148Glu APE1 and Asp312Asn XPD showed a significantly higher level of DNA incisions immediately after irradiation (p=0.049 and p=0.047 respectively) and Asp312Asn XPD showed a significantly increased capacity to repair of DNA strand breaks as measured 180min after irradiation by comet assays (p=0.004). In contrast, it was the wild type XRCC1 genotype which was associated with a lower level of DNA breaks after irradiation (p=0.014, at 180min after irradiation) and polymorphism of NBS1 did not correlate with any changes in DNA breaks or repair capacity. To confirm the influence of XPD polymorphism on repair, we established stably-transfected HCT116 (colon carcinoma) cells which over-expressed the wild-type or variant XPD protein. Cells over-expressing Asp312Asn XPD showed a higher level of DNA breaks shortly after irradiation and more efficient repair than cells over-expressing the wild-type gene XPD312Asp, and an earlier inhibition of cell cycle transit but faster recovery from this inhibition. Polymorphisms in DNA repair genes therefore influence not only DNA repair capacity but also cell proliferation, and may serve as markers of individual repair capacity and susceptibility to environmental and occupational carcinogens.
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center, Gliwice, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gdowicz-Klosok
authors.forename: Maria
authors.initials: M
authors.lastname: Widel
authors.forename: Joanna
authors.initials: J
authors.lastname: Rzeszowska-Wolny
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics*; D049109:Cell Proliferation / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D020552:Comet Assay; D004247:DNA / Q000235:genetics; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014965:X-Rays; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D004247:DNA; D051759:Xeroderma Pigmentosum Group D Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C497292:ERCC2 protein, human
keywords: APE1; Cell cycle; DNA break repair; HCT116 cells; NBS; Polymorphism; XPD; XRCC1