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

doi:10.1016/j.ccr.2012.04.038

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

59 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 language	English
Pages (from-to)	36-50
Number of pages	15
Journal	Cancer Cell
Volume	22
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2012.04.038
State	Published - 10 07 2012
Externally published	Yes

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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}",

year = "2012",

month = jul,

day = "10",

doi = "10.1016/j.ccr.2012.04.038",

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T1 - Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

AU - Hu, Chun Mei

AU - Yeh, Ming Tyng

AU - Tsao, Ning

AU - Chen, Chih Wei

AU - Gao, Quan Ze

AU - Chang, Chia Yun

AU - Lee, Ming Hsiang

AU - Fang, Jim Min

AU - Sheu, Sheh Yi

AU - Lin, Chow Jaw

AU - Tseng, Mei Chun

AU - Chen, Yu Ju

AU - Chang, Zee Fen

PY - 2012/7/10

Y1 - 2012/7/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863759637&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2012.04.038

DO - 10.1016/j.ccr.2012.04.038

M3 - 文章

C2 - 22789537

AN - SCOPUS:84863759637

SN - 1535-6108

VL - 22

SP - 36

EP - 50

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

Abstract

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