Biological and functional consequences of polymorphisms in the XPD gene

dc.contributor.advisorSherif Z.Abdel-Rahman, Ph.D.en_US
dc.contributor.committeeMemberThomas E. Albrecht, Ph.D.en_US
dc.contributor.committeeMemberRodney S. Nairn, Ph.D.en_US
dc.contributor.committeeMemberRanda A. El-Zein, MD. Ph.D.en_US
dc.contributor.committeeMemberMary Treinen-Moslen, Ph.D.en_US
dc.contributor.committeeMemberJonathan B. Ward, Ph.D.en_US
dc.creatorKevin James Wolfeen_US
dc.date.accessioned2011-12-20T16:05:27Z
dc.date.available2009-06-09en_US
dc.date.available2011-12-20T16:05:27Z
dc.date.created2006-11-07en_US
dc.date.issued2006-10-23en_US
dc.description.abstractEpidemiological studies have documented many associations between single nucleotide polymorphisms (SNPs) in the nucleotide excision repair gene XPD (ERCC2) and cancer risk. Little is known, however, about the underlying mechanisms for these associations. I used lymphocytes from healthy subjects to explore novel mechanisms which could explain the reported risk-modifying effects on disease susceptibility of three SNPs in the XPD gene, the synonymous C156A SNP in exon 6 and the nonsynonymous SNPs Asp312Asn in exon 10 and Lys751Gln in exon 23. Baseline and NNK-induced chromosomal aberrations (Ca) were assessed by cytogenetic analysis and then P values were calculated as estimates of sub-population differences for increased frequencies of CAs associated with the three XPD polymorphisms. I found significant elevation in baseline frequencies of CAs among smokers with the variant 312Asn polymorphism (P=0.028). Elevations in NNK-induced aberrations were found among younger subjects (age<39 years) with the 156A or the 751Gln polymorphism, (P=0.025 and P=0.037, respectively) and in females compared to males with a combination of the 312Asn and the 751Gln polymorphisms (P=0.045). Application of real time PCR showed that each SNP, alone and in combination, significantly decreased constitutive XPD mRNA levels (P<0.003) in lymphocytes. Decreases in XPD mRNA levels were significantly higher in older subjects and in smokers. Localized Mfold structure analysis of the mRNA sequence surrounding the studied SNPs were predicted to alter mRNA secondary structure, which indicated that these SNPs potentially affect local folding and mRNA stability. UVC treatment of cells with wild type XPD produced a significant increase (P=0.03) in XPD protein levels by 30 min, which surprisingly coincided with a decrease in XPD mRNA transcript copy number (P=0.0002). Fluorescent confocal microscopy demonstrated that this increase in XPD protein appeared largely due to an increase in nuclear localization of XPD, which was evident at 30 min and persistent at 6 hrs. New observations from this project provide possible mechanistic explanations for the association of polymorphisms in XPD with increased genetic damage (CAs) and cancer risk.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-11072006-121936en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/248
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectXPD/ERCC2en_US
dc.subjectsmokingen_US
dc.subjectRNA expressionen_US
dc.subjectpolymorphismsen_US
dc.subjectgenetic susceptibilityen_US
dc.subjectgene expressionen_US
dc.subjectDNA repairen_US
dc.subjectcanceren_US
dc.subjectbiomarkersen_US
dc.titleBiological and functional consequences of polymorphisms in the XPD geneen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentPreventive Medicine and Community Healthen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Ph.D.dissertationKevinWolfe.pdf
Size:
2.55 MB
Format:
Adobe Portable Document Format

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
891 B
Format:
Plain Text
Description: