Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair.
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.
Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 11221 Taiwan.
Chun-Mei
CM
Hu
Ming-Tyng
MT
Yeh
Ning
N
Tsao
Chih-Wei
CW
Chen
Quan-Ze
QZ
Gao
Chia-Yun
CY
Chang
Ming-Hsiang
MH
Lee
Jim-Min
JM
Fang
Sheh-Yi
SY
Sheu
Chow-Jaw
CJ
Lin
Mei-Chun
MC
Tseng
Yu-Ju
YJ
Chen
Zee-Fen
ZF
Chang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D003856:Deoxyuracil Nucleotides / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000378:metabolism
D000970:Antineoplastic Agents; D003856:Deoxyuracil Nucleotides; C027078:deoxyuridine triphosphate; D004317:Doxorubicin; D012264:Ribonucleotide Reductases; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase