Journal Article

An <i>in vivo</i> analysis of MMC-induced DNA damage and its repair

Young-Ju Lee, Su-Jung Park, Samantha L.M. Ciccone, Chong-Rak Kim and Suk-Hee Lee

in Carcinogenesis

Volume 27, issue 3, pages 446-453
Published in print March 2006 | ISSN: 0143-3334
Published online October 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi254

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Mitomycin C (MMC) induces various types of DNA damages that cause 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 (ultraviolet light A). Human wild-type 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 wild-type cells, mutant defective in XPE orXPG 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: ADR, adriamycin; BrdU, 5′-bromo-2′-deoxyuridine; CDDP, cis dichlorodiammineplatinum(II) (also known as cisplatin); DTT, dithiothreitol; ERCC, excision repair cross-complementing; 8-MOP, 8′-methoxy-psoralen; MMC, Mitomycin C; MMS, methyl methane sulphonate; NER, nucleotide excision repair; PCNA, proliferating cell nuclear antigen; RPA, replication protein A; ssDNA, single-stranded DNA; UV, ultraviolet light; XP, xeroderma pigmentosum

Journal Article.  5150 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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