Abstract
Abstract The elevation of RRM2A subunit of ribonucleotide reductase (RNR) has been shown oncogenic and associated with human cancers. However, the molecular mechanism of RRM2A in cancer promotion is unclear. In this study, we investigated whether RNR-mediated dUTP formation is involved in promoting genome instability. Since dUTP is degraded by dUTPase, we analyzed the expression of RRM2A and dUTPase in clinical samples from colorectal and breast cancer patients. The results revealed that high RRM2A and low dUTPase in tumors are correlated with poorer survival. In cancer cell lines that express high level of RRM2A and dUTPase, knockdown of dUTPase increases genome instability. Conversely, overexpression of dUTPase reduces genome stress in cancer cells expressing high RRM2A and low dUTPase. In non-tumorigenic cells, overexpression of RRM2A increases replication stress and genome instability accompanied by higher levels of 53BP1 foci and increased breaks at AT-rich fragile sites bound by 53BP1. Thymidine supplement in growth medium or co-expression of dUTPase was able to reduce RRM2A-mediated replication stress and 53BP1 foci. We further provide evidence that RRM2A promotes replication stress and error prone-translesion synthesis dependent on uracil DNA glycosylase. These results suggest that up-regulation of RRM2A in tumor cells increases uracil-mediated replication stress to promote genome instability. Therefore, high RRM2A/low dUTPase context confers tumor genome evolution advantage, correlating with poorer prognosis. Citation Format: Chih-Wei Chen, Ning Tsao, Yun Yen, Christine E. Lehman, Yuh-Hwa Wang, Chian-Feng Chen, Tse-Hsiang Wu, Sui-Chih Tien, Ming-Hsiang Lee, Zee-Fen Chang. Ribonucleotide reductase promotes uracil-mediated genome instability in tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3017. doi:10.1158/1538-7445.AM2015-3017
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