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Nucleic Acids Research 2005 33(10):3283-3291; doi:10.1093/nar/gki639
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Published online 8 June 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136

Peter H. Clingen, Inusha U. De Silva, Peter J. McHugh, Farid J Ghadessy, Michael J. Tilby1, David E. Thurston2 and John A. Hartley*

Cancer Research UK Drug–DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, UCL 91 Riding House Street, London, W1W 7BS, UK 1Northern Institute for Cancer Research, University of Newcastle Upon Tyne Medical School Newcastle Upon Tyne NE2 4HH, UK 2Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London 29-39 Brunswick Square, London WC1N 1AX, UK

*To whom correspondence should be addressed. Tel: +44 20 7679 9299; Fax: +44 20 7436 2956; Email: john.hartley{at}ucl.ac.uk

Received April 23, 2005. Accepted May 19, 2005.

SJG-136, a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer, is a highly efficient interstrand crosslinking agent that reacts with guanine bases in a 5'-GATC-3' sequence in the DNA minor groove. SJG-136 crosslinks form rapidly and persist compared to those produced by conventional crosslinking agents such as nitrogen mustard, melphalan or cisplatin which bind in the DNA major groove. A panel of Chinese hamster ovary (CHO) cells with defined defects in specific DNA repair pathways were exposed to the bi-functional agents SJG-136 and melphalan, and to their mono-functional analogues mmy-SJG and mono-functional melphalan. SJG-136 was >100 times more cytotoxic than melphalan, and the bi-functional agents were much more cytotoxic than their respective mono-functional analogues. Cellular sensitivity of both SJG-136 and melphalan was dependent on the XPF-ERCC1 heterodimer, and homologous recombination repair factors XRCC2 and XRCC3. The relative level of sensitivity of these repair mutant cell lines to SJG-136 was, however, significantly less than with major groove crosslinking agents. In contrast to melphalan, there was no clear correlation between sensitivity to SJG-136 and crosslink unhooking capacity measured using a modified comet assay. Furthermore, repair of SJG-136 crosslinks did not involve the formation of DNA double-strand breaks. SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove.

Present addresses: Inusha U. De Silva, Molecular Haematology and Cancer Biology Unit, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

Peter J. McHugh, Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK


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