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Genes 2017, 8(11), 295; doi:10.3390/genes8110295

5-Fluorouracil Treatment Alters the Efficiency of Translational Recoding

1
Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
2
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-2363, USA
3
Department of Pathology, ChangHai Hospital, Second Military Medical University, Shanghai 200433, China
4
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
*
Authors to whom correspondence should be addressed.
Received: 13 September 2017 / Revised: 17 October 2017 / Accepted: 17 October 2017 / Published: 31 October 2017
(This article belongs to the Special Issue RNA Modification)
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Abstract

5-fluorouracil (5-FU) is a chemotherapeutic agent that has been extensively studied since its initial development in the 1950s. It has been suggested that the mechanism of action of 5-FU involves both DNA- and RNA-directed processes, but this has remained controversial. In this study, using a series of in vivo reporter constructs capable of measuring translational recoding, we demonstrate that cells exposed to 5-FU display a reduced capacity to engage in a variety of translational recoding events, including +1 programmed frameshifting (PRF) and −1 PRF. In addition, 5-FU-treated cells are much less accurate at stop codon recognition, resulting in a significant increase in stop codon-readthrough. Remarkably, while the efficiency of cap-dependent translation appears to be unaffected by 5-FU, 5-FU-treated cells display a decreased ability to initiate cap-independent translation. We further show that knockdown of thymidylate synthase, an enzyme believed to be at the center of 5-FU-induced DNA damage, has no effect on the observed alterations in translational recoding. On the other hand, ribosomal RNA (rRNA) pseudouridylation, which plays an important role in translational recoding, is significantly inhibited. Taken together, our results suggest that the observed effect of 5-FU on recoding is an RNA-directed effect. Our results are the first to show definitely and quantitatively that translational recoding is affected by exposure to 5-FU. Thus, it is possible that a substantial portion of 5-FU cytotoxicity might possibly be the result of alterations in translational recoding efficiency. View Full-Text
Keywords: 5-Fluorouracil; translational recoding; internal ribosome entry site; programmed frameshifting; nonsense suppression; RNA pseudouridylation 5-Fluorouracil; translational recoding; internal ribosome entry site; programmed frameshifting; nonsense suppression; RNA pseudouridylation
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MDPI and ACS Style

Ge, J.; Karijolich, J.; Zhai, Y.; Zheng, J.; Yu, Y.-T. 5-Fluorouracil Treatment Alters the Efficiency of Translational Recoding. Genes 2017, 8, 295.

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