The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells

Chih Wei Chen; Ning Tsao; Lin Yi Huang; Yun Yen; Xiyong Liu; Christine Lehman; Yuh Hwa Wang; Mei Chun Tseng; Yu Ju Chen; Yi Chi Ho; Chian Feng Chen; Zee Fen Chang

doi:10.1016/j.celrep.2016.06.094

The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells

Chih Wei Chen, Ning Tsao, Lin Yi Huang, Yun Yen, Xiyong Liu, Christine Lehman, Yuh Hwa Wang, Mei Chun Tseng, Yu Ju Chen, Yi Chi Ho, Chian Feng Chen, Zee Fen Chang

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

21 Citations (Scopus)

Abstract

The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.

Original language	English
Pages (from-to)	1287-1299
Number of pages	13
Journal	Cell Reports
Volume	16
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2016.06.094
Publication status	Published - Aug 2 2016

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.06.094

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title = "The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells",

abstract = "The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.",

author = "Chen, {Chih Wei} and Ning Tsao and Huang, {Lin Yi} and Yun Yen and Xiyong Liu and Christine Lehman and Wang, {Yuh Hwa} and Tseng, {Mei Chun} and Chen, {Yu Ju} and Ho, {Yi Chi} and Chen, {Chian Feng} and Chang, {Zee Fen}",

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doi = "10.1016/j.celrep.2016.06.094",

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AU - Chen, Chih Wei

AU - Tsao, Ning

AU - Huang, Lin Yi

AU - Yen, Yun

AU - Liu, Xiyong

AU - Lehman, Christine

AU - Wang, Yuh Hwa

AU - Tseng, Mei Chun

AU - Chen, Yu Ju

AU - Ho, Yi Chi

AU - Chen, Chian Feng

AU - Chang, Zee Fen

PY - 2016/8/2

Y1 - 2016/8/2

N2 - The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.

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The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells

Abstract

ASJC Scopus subject areas

UN SDGs

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