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Nojima, K.* ; Arakawa, H. ; Buerstedde, J.-M.

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

Cancer Res. 65, 11704-11711 (2005)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polζ, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Zeitschrift Cancer Research
Quellenangaben Band: 65, Heft: 24, Seiten: 11704-11711 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Radiation Biology (IMS)