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Article

Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis

1
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, NO-7489 Trondheim, Norway
2
West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, P.O. BOX LG 54 Accra, Ghana
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Department of Biochemistry, Cell and Molecular Biology, University of Ghana, P.O. BOX LG 54 Accra, Ghana
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Department of Biotechnology and Food Science, Faculty of Natural Sciences, NTNU Norwegian University of Science and Technology, NO-7481 Trondheim, Norway
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Proteomics and Modomics Experimental Core Facility (PROMEC), NTNU Norwegian University of Science and Technology, NO-7481 Trondheim, Norway
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Department of Medical Microbiology, University of Ghana Medical School, P.O. Box 4236 Accra, Ghana
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Clinic of Laboratory medicine, St. Olav University Hospital, NO-7006 Trondheim, Norway
*
Author to whom correspondence should be addressed.
Academic Editor: Udi Qimron
Biomolecules 2021, 11(6), 843; https://doi.org/10.3390/biom11060843
Received: 21 April 2021 / Revised: 1 June 2021 / Accepted: 2 June 2021 / Published: 5 June 2021
(This article belongs to the Section Molecular Biology)
Drugs targeting DNA and RNA in mammalian cells or viruses can also affect bacteria present in the host and thereby induce the bacterial SOS system. This has the potential to increase mutagenesis and the development of antimicrobial resistance (AMR). Here, we have examined nucleoside analogues (NAs) commonly used in anti-viral and anti-cancer therapies for potential effects on mutagenesis in Escherichia coli, using the rifampicin mutagenicity assay. To further explore the mode of action of the NAs, we applied E. coli deletion mutants, a peptide inhibiting Pol V (APIM-peptide) and metabolome and proteome analyses. Five out of the thirteen NAs examined, including three nucleoside reverse transcriptase inhibitors (NRTIs) and two anti-cancer drugs, increased the mutation frequency in E. coli by more than 25-fold at doses that were within reported plasma concentration range (Pl.CR), but that did not affect bacterial growth. We show that the SOS response is induced and that the increase in mutation frequency is mediated by the TLS polymerase Pol V. Quantitative mass spectrometry-based metabolite profiling did not reveal large changes in nucleoside phosphate or other central carbon metabolite pools, which suggests that the SOS induction is an effect of increased replicative stress. Our results suggest that NAs/NRTIs can contribute to the development of AMR and that drugs inhibiting Pol V can reverse this mutagenesis. View Full-Text
Keywords: NA; NRTIs; β-clamp; SOS; Pol V; TLS; AMR; MDR NA; NRTIs; β-clamp; SOS; Pol V; TLS; AMR; MDR
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MDPI and ACS Style

Sumabe, B.K.; Ræder, S.B.; Røst, L.M.; Sharma, A.; Donkor, E.S.; Mosi, L.; Duodu, S.; Bruheim, P.; Otterlei, M. Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis. Biomolecules 2021, 11, 843. https://doi.org/10.3390/biom11060843

AMA Style

Sumabe BK, Ræder SB, Røst LM, Sharma A, Donkor ES, Mosi L, Duodu S, Bruheim P, Otterlei M. Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis. Biomolecules. 2021; 11(6):843. https://doi.org/10.3390/biom11060843

Chicago/Turabian Style

Sumabe, Balagra K., Synnøve B. Ræder, Lisa M. Røst, Animesh Sharma, Eric S. Donkor, Lydia Mosi, Samuel Duodu, Per Bruheim, and Marit Otterlei. 2021. "Nucleoside Analogues Are Potent Inducers of Pol V-mediated Mutagenesis" Biomolecules 11, no. 6: 843. https://doi.org/10.3390/biom11060843

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