This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jiang, H. Articles by Yang, L.-Y. Search for Related Content PubMed PubMed Citation Articles by Jiang, H. Articles by Yang, L.-Y.

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.

This article has been cited by other articles:

				M. J. Edelman, K. S. Bauer Jr., S. Wu, R. Smith, S. Bisacia, and J. Dancey Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2667 - 2674. [Abstract] [Full Text] [PDF]

				X. Wu, S. M. Shell, Z. Yang, and Y. Zou Phosphorylation of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A by Ataxia Telangiectasia Mutated and Rad3-Related-Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation. Cancer Res., March 15, 2006; 66(6): 2997 - 3005. [Abstract] [Full Text] [PDF]

				Y. Seo, T. Yan, J. E. Schupp, K. Yamane, T. Radivoyevitch, and T. J. Kinsella The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine Cancer Res., January 1, 2006; 66(1): 490 - 498. [Abstract] [Full Text] [PDF]

				T. D. Bradshaw, C. S. Matthews, J. Cookson, E.-H. Chew, M. Shah, K. Bailey, A. Monks, E. Harris, A. D. Westwell, G. Wells, et al. Elucidation of Thioredoxin as a Molecular Target for Antitumor Quinols Cancer Res., May 1, 2005; 65(9): 3911 - 3919. [Abstract] [Full Text] [PDF]

				R. V. N. Lord, J. Brabender, D. Gandara, V. Alberola, C. Camps, M. Domine, F. Cardenal, J. M. Sanchez, P. H. Gumerlock, M. Taron, et al. Low ERCC1 Expression Correlates with Prolonged Survival after Cisplatin plus Gemcitabine Chemotherapy in Non-Small Cell Lung Cancer Clin. Cancer Res., July 1, 2002; 8(7): 2286 - 2291. [Abstract] [Full Text] [PDF]

				T. Yamauchi, M. J. Keating, and W. Plunkett UCN-01 (7-Hydroxystaurosporine) Inhibits DNA Repair and Increases Cytotoxicity in Normal Lymphocytes and Chronic Lymphocytic Leukemia Lymphocytes Mol. Cancer Ther., February 1, 2002; 1(4): 287 - 294. [Abstract] [Full Text] [PDF]

				G. M. Hellmann, W. R. Fields, and D. J. Doolittle Gene Expression Profiling of Cultured Human Bronchial Epithelial and Lung Carcinoma Cells Toxicol. Sci., May 1, 2001; 61(1): 154 - 163. [Abstract] [Full Text] [PDF]

				E. Rosenberg, M. M. Taher, N. B. Kuemmerle, J. Farnsworth, and K. Valerie A Truncated Human Xeroderma Pigmentosum Complementation Group A Protein Expressed from an Adenovirus Sensitizes Human Tumor Cells to Ultraviolet Light and Cisplatin Cancer Res., January 1, 2001; 61(2): 764 - 770. [Abstract] [Full Text]