The Protein Journal

, Volume 26, Issue 8, pp 541–546 | Cite as

Conformational Effects of a Common Codon 399 Polymorphism on the BRCT1 Domain of the XRCC1 Protein

  • Regina Monaco
  • Ramon Rosal
  • Michael A. Dolan
  • Matthew R. Pincus
  • Paul W. Brandt-Rauf


The X-ray cross-complementing-1 (XRCC1) protein functions as a scaffold that coordinates the activity of the cellular machinery involved in base excision repair (BER) of DNA damage. The BRCT1 domain of XRCC1 is responsible for interacting with several of the key components of the BER machinery, and it is also the site of a common genetic polymorphism in XRCC1 at amino acid residue 399 (Arg → Gln). Experimental and epidemiologic evidence suggest that this polymorphism may alter BER capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XRCC1 induced by the polymorphism. Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the BRCT1 domain of XRCC1, and differences in structure produced by the polymorphic substitution were determined. The results indicate that, although the general configuration of both proteins is similar and there is little actual deviation at the site of the polymorphism itself, the substitution produces significant conformational changes at several other sites in the BRCT1 domain, including the loss of secondary structural features such as α helices that may be critical for protein–protein interactions. These results provide support for the hypothesis that this polymorphism in XRCC1 could affect DNA repair capability by altering the structure of the BRCT1 domain and thus the ability of XRCC1 to coordinate BER.


Genetic polymorphism Structure–function correlation Base excision repair Molecular dynamics 



X-ray cross-complementing-1


Base excision repair


BRCA1 carboxy terminus


Poly(ADP-ribose) polymerase


human 8-oxoguanine glycosylase


Methyl purine glycosylase


Apurinic/apyrimidinic endonuclease 1

Pol β

DNA polymerase β


DNA ligase III


N-terminal domain



This work was supported in part by grants from NIEHS (P30-ES09089) and NIOSH (R01-OH04192).


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Regina Monaco
    • 1
  • Ramon Rosal
    • 1
    • 2
  • Michael A. Dolan
    • 3
  • Matthew R. Pincus
    • 4
  • Paul W. Brandt-Rauf
    • 1
  1. 1.Department of Environmental Health Sciences, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  2. 2.Chemical Terrorism LaboratoryNew York City Department of Health and Mental HygieneNew YorkUSA
  3. 3.Tripos, IncSt. LouisUSA
  4. 4.Department of Pathology and Laboratory MedicineNew York Harbor VA Medical CenterBrooklynUSA

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