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Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

Authors :
Hu, Chun-Mei
Yeh, Ming-Tyng
Tsao, Ning
Chen, Chih-Wei
Gao, Quan-Ze
Chang, Chia-Yun
Lee, Ming-Hsiang
Fang, Jim-Min
Sheu, Sheh-Yi
Lin, Chow-Jaw
Tseng, Mei-Chun
Chen, Yu-Ju
Chang, Zee-Fen
Source :
Cancer Cell. Jul2012, Vol. 22 Issue 1, p36-50. 15p.
Publication Year :
2012

Abstract

Summary: 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 &y& Elsevier]

Details

Language :
English
ISSN :
15356108
Volume :
22
Issue :
1
Database :
Academic Search Index
Journal :
Cancer Cell
Publication Type :
Academic Journal
Accession number :
77732534
Full Text :
https://doi.org/10.1016/j.ccr.2012.04.038