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Conformational effects of a common codon 399 polymorphism on the BRCT1 domain of the XRCC1 protein.

Authors
Monaco-R; Rosal-R; Dolan-MA; Pincus-MR; Brandt-Rauf-PW
Source
Protein J 2007 Dec; 26(8):541-546
NIOSHTIC No.
20033206
Abstract
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.
Keywords
Genes; Genetics; Genetic-factors; Genetic-disorders; Mutagenesis; Mutagenicity; Mutagens; Cell-alteration; Cell-biology; Cell-metabolism; Cell-morphology; Cellular-reactions; Cell-function; Cellular-structures; Protein-biochemistry; Protein-synthesis; Proteins
Contact
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
CODEN
JPCHD2
Publication Date
20071201
Document Type
Journal Article
Email Address
pwb1@columbia.edu
Funding Amount
163500
Funding Type
Grant
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-004192
Issue of Publication
8
ISSN
1572-3887
Source Name
The Protein Journal
State
NY
Performing Organization
Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York
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