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Conformational effects of a common codon 751 polymorphism on the C-terminal domain of the xeroderma pigmentosum D protein.

Authors
Monaco-R; Rosal-R; Dolan-MA; Pincus-MR; Freyer-G; Brandt-Rauf-PW
Source
J Carcinog 2009 Aug; 8:12
NIOSHTIC No.
20042205
Abstract
Aim: The xeroderma pigmentosum D (XPD) protein is a DNA helicase involved in the repair of DNA damage, including nucleotide excision repair (NER) and transcription-coupled repair (TCR). The C-terminal domain of XPD has been implicated in interactions with other components of the TFIIH complex, and it is also the site of a common genetic polymorphism in XPD at amino acid residue 751 (Lys->Gln). Some evidence suggests that this polymorphism may alter DNA repair capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XPD induced by the polymorphism. Materials and Methods: Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the C-terminal domain of XPD and differences in structure produced by the polymorphic substitution were determined. Results: The results indicate that, although the general configuration of both proteins is similar, the substitution produces a significant conformational change immediately N-terminal to the site of the polymorphism. Conclusion: These results provide support for the hypothesis that this polymorphism in XPD could affect DNA repair capability, and hence cancer risk, by altering the structure of the C-terminal domain.
Keywords
Proteins; Cell-function; Cellular-function; Genetics; Cancer; Risk-factors; Exposure-levels; Molecular-structure; Author Keywords: Genetic polymorphism; structure-function correlation; nucleotide excision repair; molecular dynamics
Contact
Paul W Brandt-Rauf, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Room 1145, Chicago, IL 60612
Publication Date
20090806
Document Type
Journal Article
Funding Type
Grant
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-004192
ISSN
0974-6773
Source Name
Journal of Carcinogenesis
State
IL; MO; NY
Performing Organization
University of Illinois
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