ALBERT

Description: Publication date: Available online 21 July 2016 Source: Cell Reports Author(s): 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 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. Graphical abstract Teaser Chen et al. show that the expression of dUTPase determines whether elevation of the ribonucleotide reductase subunit R2 can lead to genome stress and chromosomal instability. Furthermore, the combination of low dUTPase and high R2 in clinical tumor samples predicts poor survival in patients with colorectal cancer or breast cancers.