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Cell Cycle Checkpoint Abrogator UCN-01 Inhibits DNA Repair

Association with Attenuation of the Interaction of XPA and ERCC1 Nucleotide Excision Repair Proteins¹

Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

UCN-01, an anticancer agent currently in Phase I clinical trials, has been found to potentiate the cytotoxicity of cisplatin (CDDP). Because mammalian cells remove CDDP-induced DNA adducts through the nucleotide excision repair (NER) pathway, we determined the effects of UCN-01 on NER by measuring its effects on the interaction of the repair factors XPA and ERCC1 and the phosphorylation/dephosphorylation of the repair proteins. The repair activity, as measured by an in vitro repair synthesis assay and an in vivo host-cell reactivation assay using A549 cells, was significantly reduced. Although expression of XPA and ERCC1 proteins was elevated in cells exposed to UCN-01, the treatment resulted in a decreased ERCC1 level in the Triton X-100-insoluble fraction of cell lysates. A pull-down assay using the MBP-XPA fusion protein showed a significant reduction in the binding of ERCC1 to XPA in nuclear extracts from UCN-01-treated cells compared with untreated cells, suggesting that UCN-01 reduced the XPA-ERCC1 interaction. Consistent with these data, lower repair incision activity was found in the cell extracts from UCN-01-treated cells. In vitro phosphorylation revealed that UCN-01 had no effect on the phosphorylation/dephosphorylation status of either XPA or ERCC1; however, UCN-01 caused dephosphorylation of an unidentified XPA-bound protein with an apparent molecular mass of 52 kDa. Taken together, these data demonstrate the NER-inhibitory action of UCN-01, which is associated with the inhibition of the XPA-ERCC1 interaction by UCN-01 and with the effect of UCN-01 on the phosphorylation/dephosphorylation of an XPA-bound, 52-kDa protein, the identity of which remains to be determined.

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