Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair.

Chun-Mei Hu, Ming-Tyng Yeh, Ning Tsao, Chih-Wei Chen, Quan-Ze Gao, Chia-Yun Chang, Ming-Hsiang Lee, Jim-Min Fang, Sheh-Yi Sheu, Chow-Jaw Lin, Mei-Chun Tseng, Yu-Ju Chen, Zee-Fen Chang

Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 11221 Taiwan.

Cancer cell 2012 Jul 10

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The synthesis of dTDP is unique because there is a requirement for thymidylate kinase (TMPK). All other dNDPs including dUDP are directly produced by ribonucleotide reductase (RNR). We report the binding of TMPK and RNR at sites of DNA damage. In tumor cells, when TMPK function is blocked, dUTP is incorporated during DNA double-strand break (DSB) repair. Disrupting RNR recruitment to damage sites or reducing the expression of the R2 subunit of RNR prevents the impairment of DNA repair by TMPK intervention, indicating that RNR contributes to dUTP incorporation during DSB repair. We identified a cell-permeable nontoxic inhibitor of TMPK that sensitizes tumor cells to doxorubicin in vitro and in vivo, suggesting its potential as a therapeutic option. Copyright © 2012 Elsevier Inc. All rights reserved.

Citation

Chun-Mei Hu, Ming-Tyng Yeh, Ning Tsao, Chih-Wei Chen, Quan-Ze Gao, Chia-Yun Chang, Ming-Hsiang Lee, Jim-Min Fang, Sheh-Yi Sheu, Chow-Jaw Lin, Mei-Chun Tseng, Yu-Ju Chen, Zee-Fen Chang. Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair. Cancer cell. 2012 Jul 10;22(1):36-50