Abstract B36: The role of dUTPase in ribonucleotide reductase-driven tumorigenesis and tumor progression

Abstract

Abstract Regulation of enzymes in nucleotide synthesis plays a critical role in DNA replication and repair. Ribonucleotide reductase (RNR) is the key enzyme that controls the de novo synthesis of all four dNTPs, and the expression of RRM2 subunit of RNR is often elevated in malignant tumor cells. Our previous study has demonstrated that RNR contributes to dUTP mis-incorporation in DNA repair when dTTP supply is deficient. In this study, we investigated the relationship between the expression level of RRM2 and dUTP pyrophosphatase(dUTPase) and tumor progression. Immunohistochemistry staining of surgical tumors from colorectal cancer (CRC) patients showed that high RRM2/low dUTPase correlates with poorer overall survival. We further analyzed the interplay of RRM2 and dUTPase in genome stress and cellular transformation. Our results revealed that constitutive elevation of RRM2 in normal fibroblasts promotes replication stress, as indicated by 53BP foci, and cellular transformation, both of which are prevented by co-expression of dUTPase. Knockdown of dUTPase in cancer cells containing high levels of RRM2 and dUTPase also increased replication stress. We proposed that the context of high RRM2/low dUTPase confers cancer cells replication stress to drive tumorigenesis and might serve as a prognostic indicator. Citation Format: Zee-Fen Chang. The role of dUTPase in ribonucleotide reductase-driven tumorigenesis and tumor progression. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B36.