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

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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.

Original languageEnglish
Pages (from-to)36-50
Number of pages15
JournalCancer Cell
Volume22
Issue number1
DOIs
StatePublished - Jul 10 2012

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