@article{919ef2bfd4364af39ad8f6ee4ac686bc,
title = "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.",
author = "Hu, {Chun Mei} and Yeh, {Ming Tyng} and Ning Tsao and Chen, {Chih Wei} and Gao, {Quan Ze} and Chang, {Chia Yun} and Lee, {Ming Hsiang} and Fang, {Jim Min} and Sheu, {Sheh Yi} and Lin, {Chow Jaw} and Tseng, {Mei Chun} and Chen, {Yu Ju} and Chang, {Zee Fen}",
note = "Funding Information: We thank B. Vogelstein (The Johns Hopkins University Medical Institutions), M.B. Kastan (St. Jude Children's Research Hospital, Memphis), A.J. Pierce (University of Kentucky, Lexington), S.Y. Shieh (Institute of Biomedical Sciences, Academia Sinica, Taiwan), C.H. Lin (Institute of Biological Chemistry, Academia Sinica, Taiwan), W.H. Lee (Department of Biological Chemistry University of California, Irvine USA), C.L. Hsieh (Graduate Institute of Cancer Biology, China Medical University Hospital, Taiwan), and O.K. Lee (Stem Cell Research Center, National Yang-Ming University, Taiwan) for providing p53 +/+ , p53 −/− HCT-116 cell lines, I-PpoI, the I-SceI expression vectors, the U2OS stably expressing DR-GFP reporter, Capan-1, HCC1937, MCF-10A H184B5F5/M10, HRCE, and HBMSC, respectively. The authors are indebted to Y.J. Lee, P.S. Jiang, and T.Y. Huang at National Yang-Ming University for their technical assistance and P.-Y. Lin (Mass spectrometry facility, Academia Sinica, Taiwan) for her help in mass spectrum analysis. We are also grateful to C.H. Wong and Y.T. Wu (Genome Center, Academia Sinica) for generously providing the chemical library and technical support. This study was supported by grants NHRI-EX-100-10005NI from National Health Research Institute and NSC 100-2325-B-010-001 from National Science Council, Taiwan, and a grant from Aim for the Top University plan in National Yang-Ming University supported by the Ministry of Education, Taiwan. ",
year = "2012",
month = jul,
day = "10",
doi = "10.1016/j.ccr.2012.04.038",
language = "English",
volume = "22",
pages = "36--50",
journal = "Cancer Cell",
issn = "1535-6108",
number = "1",
}