Repair of mitomycin C mono- and interstrand cross-linked DNA adducts by UvrABC: a new model |
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| Authors: | Mao-wen Weng Yi Zheng Vijay P. Jasti Elise Champeil Maria Tomasz Yinsheng Wang Ashis K. Basu Moon-shong Tang |
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| Affiliation: | 1.Department of Environmental Medicine, Pathology, and Medicine, New York University School of Medicine, Tuxedo, New York 10987, 2.Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, 3.Department of Science, John Jay College, City University of New York, New York 10019, 4.Department of Chemistry, Hunter College, City University of New York, New York, New York 10021 and 5.Department of Chemistry, University of California, Riverside, CA 92521, USA |
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| Abstract: | Mitomycin C induces both MC-mono-dG and cross-linked dG-adducts in vivo. Interstrand cross-linked (ICL) dG-MC-dG-DNA adducts can prevent strand separation. In Escherichia coli cells, UvrABC repairs ICL lesions that cause DNA bending. The mechanisms and consequences of NER of ICL dG-MC-dG lesions that do not induce DNA bending remain unclear. Using DNA fragments containing a MC-mono-dG or an ICL dG-MC-dG adduct, we found (i) UvrABC incises only at the strand containing MC-mono-dG adducts; (ii) UvrABC makes three types of incisions on an ICL dG-MC-dG adduct: type 1, a single 5′ incision on 1 strand and a 3′ incision on the other; type 2, dual incisions on 1 strand and a single incision on the other; and type 3, dual incisions on both strands; and (iii) the cutting kinetics of type 3 is significantly faster than type 1 and type 2, and all of 3 types of cutting result in producing DSB. We found that UvrA, UvrA + UvrB and UvrA + UvrB + UvrC bind to MC-modified DNA specifically, and we did not detect any UvrB- and UvrB + UvrC–DNA complexes. Our findings challenge the current UvrABC incision model. We propose that DSBs resulted from NER of ICL dG-MC-dG adducts contribute to MC antitumor activity and mutations. |
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