Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells.
Polymorphisms in several DNA repair genes have recently been identified, but little is known about their phenotypic significance. To determine whether variation in DNA repair genes is related to host DNA damage, we studied the association between polymorphisms in XRCC1 (codon 399) and ERCC2 (codon 751) and two markers of DNA damage, sister chromatid exchange (SCE) frequencies (n = 76) and polyphenol DNA adducts (n = 61). SCE frequencies were determined using a modified fluorescence-Giemsa method and polyphenol DNA adducts were determined using a P1-enhanced (32)P-post-labeling procedure. XRCC1 and ERCC2 genotypes were identified using PCR-RFLP. Mean SCE frequencies among current smokers who were homozygous carriers of the 399Gln allele in XRCC1 were greater than those in 399Arg/Arg current smokers. We also observed a possible gene-dosage effect for XRCC1 399Gln and detectable DNA adducts, and significantly more adducts among older subjects who were carriers of the 399Gln allele than in younger subjects with the 399Arg/Arg genotype. The polymorphism in ERCC2 was unrelated to SCE frequency or DNA adduct level. Our results suggest that carriers of the polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age-related DNA damage.
Duell
E J
EJ
Department of Cancer Cell Biology and Occupational Health Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Wiencke
J K
JK
Cheng
T J
TJ
Varkonyi
A
A
Zuo
Z F
ZF
Ashok
T D
TD
Mark
E J
EJ
Wain
J C
JC
Christiani
D C
DC
Kelsey
K T
KT
D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D004249:DNA Damage; D004265:DNA Helicases; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D012854:Sister Chromatid Exchange; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein
D017931:DNA Primers; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011506:Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human