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

Abstract

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 22 Issue 1 Pg. 36-50 (Jul 10 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 22789537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Deoxyuracil Nucleotides
• deoxyuridine triphosphate
• Doxorubicin
• Ribonucleotide Reductases
• Nucleoside-Phosphate Kinase
• dTMP kinase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• DNA Damage
• DNA Repair
• Deoxyuracil Nucleotides (metabolism)
• Doxorubicin (pharmacology)
• Female
• Mice
• Mice, Inbred BALB C
• Nucleoside-Phosphate Kinase (antagonists & inhibitors, metabolism)
• Ribonucleotide Reductases (metabolism)