Regina Monaco1, Ramon Rosal2, Michael A Dolan3, Matthew R Pincus4, Greg Freyer1, Paul W Brandt-Rauf5
1 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
2 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University; Chemical Terrorism Laboratory, New York City Department of Health and Mental Hygiene, New York, NY 10016, USA
3 Tripos, Inc., St. Louis, MO 63144, USA
4 Department of Pathology and Laboratory Medicine, New York Harbor VA Medical Center, Brooklyn, NY 12209, USA
5 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
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: Genetic polymorphism, structure-function correlation, nucleotide excision repair, molecular dynamics