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

Details

• Personal Author:
  Brandt-Rauf PW ; Dolan MA ; Monaco R ; Pincus MR ; Rosal R
• Description:
  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 alpha 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. [Description provided by NIOSH]
• Subjects:
  Genetics Mutagens Occupational Health Safety
• Keywords:
  Cell-alteration Cell-biology Cell-function Cell-metabolism Cell-morphology Cellular-reactions Cellular-structures Genes Genetic-disorders Genetic-factors Mutagenesis Mutagenicity Protein-biochemistry Protein-synthesis Proteins

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• ISSN:
  1572-3887
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  26
• Issue:
  8
• NIOSHTIC Number:
  nn:20033206
• Citation:
  Protein J 2007 Dec; 26(8):541-546
• Contact Point Address:
  Paul W. Brandt-Rauf Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY 10032
• Email:
  pwb1@columbia.edu
• Federal Fiscal Year:
  2008
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York
• Peer Reviewed:
  True
• Start Date:
  20010701
• Source Full Name:
  The Protein Journal
• End Date:
  20150831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4f42c25e3f1ebeb7be6aa0b2e6f8d099b6fff0576bfd92c069f429d121c1641e01ea0aa9b7267ab8749ad75b76b4cc53c0f5bb7004c81e2fc3877a773e3c8895
• Download URL:
  https://stacks.cdc.gov/view/cdc/188874/cdc_188874_DS1.pdf
• File Type:
  [PDF - 318.43 KB ]