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.

Clingen, P; De Silva, I; McHugh, P; Ghadessy, F; Tilby, M; Thurston, D; Hartley, J

Women's Health Collection

Journal 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.

Abstract:: 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.

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APA Style

Clingen, P., De Silva, I., McHugh, P., Ghadessy, F., Tilby, M., Thurston, D., & Hartley, J. (2005). 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. Nucleic Acids Research, 33(10), 3283–3291.

MLA Style

Clingen, P, et al. “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.” Nucleic Acids Research, vol. 33, no. 10, 2005, pp. 3283–91.

Chicago Style

Clingen, P, I De Silva, P McHugh, et al. 2005. “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.” Nucleic Acids Research 33 (10): 3283–91.
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