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Carcinogenesis Advance Access published online on October 29, 2005
Carcinogenesis, doi:10.1093/carcin/bgi254
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 18, 2005
Revised September 27, 2005
Accepted October 26, 2005

CANCER BIOLOGY

An in vivo analysis of MMC-induced DNA damage and its repair

Young-Ju Lee 1, Su-Jung Park 2, Samantha L. M. Ciccone 3, Chong-Rak Kim 4, and Suk-Hee Lee 2*

1 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202
3 Department of Microbiology, Indiana University School of Medicine, Indianapolis, Indiana 46202
4 Inje University, Kimhae, Korea

* To whom correspondence should be addressed.
Suk-Hee Lee, E-mail: slee{at}iupui.edu


  Abstract

Mitomycin (MMC) induces various types of DNA damages that cause a significant cytotoxicity to cells. Accordingly, repair of MMC-induced damages involves multiple repair pathways such as nucleotide-excision repair, homologous recombination repair, and translesion bypass repair pathways. Nonetheless, repair of the MMC-induced DNA damages in mammals have not been fully delineated. In this study, we investigated potential roles for Xeroderma pigmentosum (XP) proteins in the repair of MMC-induced DNA damages using an assay that detects the ssDNA patches generated following treatment with MMC or 8-methoxy-psoralen (8-MOP) + UVA. Human wildtype cells formed distinctive ssDNA foci following treatment with MMC or 8-MOP + UVA, but not with those inducing alkylation damage, oxidative damage, or strand-break damage, suggesting that the foci represent ssDNA patches formed during the crosslink repair. In contrast to wildtype cells, mutants defective in XPE and XPG did not form the ssDNA foci following MMC treatment, while XPF mutant cells showed a significantly delayed response in forming the foci. A positive role for XPG in the repair of MMC-induced DNA damages was further supported by observations that cells treated with MMC induced a tight association of XPG with chromatin, and a targeted inhibition of XPG abolished MMC-induced ssDNA foci formation, rendering cells hypersensitive to MMC. Together, our results suggest that XPG along with XPE and XPF play unique role(s) in the repair of MMC-induced DNA damages.

Keywords: crosslink DNA damage; mitomycin c; psoralen; DNA repair; Xeroderma pigmentosum.
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