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

研究成果: 雜誌貢獻文章

11 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)1287-1299
頁數13
期刊Cell Reports
16
發行號5
DOIs
出版狀態已發佈 - 八月 2 2016

    指紋

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

引用此

Chen, C. W., Tsao, N., Huang, L. Y., Yen, Y., Liu, X., Lehman, C., Wang, Y. H., Tseng, M. C., Chen, Y. J., Ho, Y. C., Chen, C. F., & Chang, Z. F. (2016). The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells. Cell Reports, 16(5), 1287-1299. https://doi.org/10.1016/j.celrep.2016.06.094