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Nucleic Acids Research, 2000, Vol. 28, No. 10 2049-2059
© 2000 Oxford University Press

Domain specific interaction in the XRCC1–DNA polymerase ß complex

Assen Marintchev, Anthony Robertson1, Emilios K. Dimitriadis2, Rajendra Prasad1, Samuel H. Wilson1 and Gregory P. Mullen*

Department of Biochemistry, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06032, USA 1Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA and 2Biomedical Engineering and Physical Sciences Program, National Institutes of Health, Bethesda, MD 20892, USA

XRCC1 (X-ray cross-complementing group 1) is a DNA repair protein that forms complexes with DNA polymerase ß (ß-Pol), DNA ligase III and poly-ADP-ribose polymerase in the repair of DNA single strand breaks. The domains in XRCC1 have been determined, and characterization of the domain–domain interaction in the XRCC1-ß-Pol complex has provided information on the specificity and mechanism of binding. The domain structure of XRCC1, determined using limited proteolysis, was found to include an N-terminal domain (NTD), a central BRCT-I (breast cancer susceptibility protein-1) domain and a C-terminal BRCT-II domain. The BRCT-I–linker–BRCT-II C-terminal fragment and the linker–BRCT-II C-terminal fragment were relatively stable to proteolysis suggestive of a non-random conformation of the linker. A predicted inner domain was found not to be stable to proteolysis. Using cross-linking experiments, XRCC1 was found to bind intact ß-Pol and the ß-Pol 31 kDa domain. The XRCC1-NTD1–183 (residues 1–183) was found to bind ß-Pol, the ß-Pol 31 kDa domain and the ß-Pol C-terminal palm-thumb (residues 140–335), and the interaction was further localized to XRCC1-NTD1–157 (residues 1–157). The XRCC1-NTD1–183-ß-Pol 31 kDa domain complex was stable at high salt (1 M NaCl) indicative of a hydrophobic contribution. Using a yeast two-hybrid screen, polypeptides expressed from two XRCC1 constructs, which included residues 36–355 and residues 1–159, were found to interact with ß-Pol, the ß-Pol 31 kDa domain, and the ß-Pol C-terminal thumb-only domain polypeptides expressed from the respective ß-Pol constructs. Neither the XRCC1-NTD1–159, nor the XRCC136–355 polypeptide was found to interact with a ß-Pol thumbless polypeptide. A third XRCC1 polypeptide (residues 75–212) showed no interaction with ß-Pol. In quantitative gel filtration and analytical ultracentrifugation experiments, the XRCC1-NTD1–183 was found to bind ß-Pol and its 31 kDa domain in a 1:1 complex with high affinity (Kd of 0.4–2.4 µM). The combined results indicate a thumb-domain specific 1:1 interaction between the XRCC1-NTD1–159 and ß-Pol that is of an affinity comparable to other binding interactions involving ß-Pol.

* To whom correspondence should be addressed. Tel: +1 860 679 1943; Fax: +1 860 679 3408; Email: gmullen@panda.uchc.edu


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