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


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.


CONCLUSIONS
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.
Monaco
Regina
R
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032; Division of Environmental and Occupational Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL 60612, USA. pwb1@uic.edu.
Rosal
Ramon
R
Dolan
Michael A
MA
Pincus
Matthew R
MR
Freyer
Greg
G
Brandt-Rauf
Paul W
PW