Insights into the base-pairing preferences of 8-oxoguanosine on the ribosome

Thomas, Erica N.; Simms, Carrie L.; Keedy, Hannah; Zaher, Hani

doi:10.1093/nar/gkz701

Cited by 23 publications

(22 citation statements)

References 72 publications

(77 reference statements)

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“…Since compensatory measures are often induced in response to antibiotic stress, we hypothesize that ribosome rescue is of particular importance for the ability of B. subtilis to deal with mRNAs affected by oxidative stress. It has been shown that mRNAs are prime targets of oxidation by reactive oxygen species and that ribosomes stall on oxidized mRNAs when decoding is prevented ( 50 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

Senges

Stepanek

Wenzel

et al. 2020

Antimicrob Agents Chemother

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New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. The Comparison of Proteomic Responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.

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Section: Discussionmentioning

confidence: 99%

Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

Senges

Stepanek

Wenzel

et al. 2020

Antimicrob Agents Chemother

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“…The fact that templates containing 8-BrI do not lead to cDNA synthesis, while those containing I do, implies that the bromine may be posing adverse interactions that may prevent protein:RNA contacts that affect transcription efficiency. Pointing out to the importance of having these interactions intact and that the conformation and H-bonding between base pairs is not sufficient to dictate enzymatic reactivity, since other aspects and changes in structure must be taken in consideration [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Translesion synthesis by AMV, HIV, and MMLVreverse transcriptases using RNA templates containing inosine, guanosine, and their 8-oxo-7,8-dihydropurine derivatives

et al. 2020

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Inosine is ubiquitous and essential in many biological processes, including RNA-editing. In addition, oxidative stress on RNA has been a topic of increasing interest due, in part, to its potential role in the development/progression of disease. In this work we probed the ability of three reverse transcriptases (RTs) to catalyze the synthesis of cDNA in the presence of RNA templates containing inosine (I), 8-oxo-7,8-dihydroinosine (8oxo-I), guanosine (G), or 8-oxo-7,8-dihydroguanosine (8-oxoG), and explored the impact that these purine derivatives have as a function of position. To this end, we used 29-mers of RNA (as template) containing the modifications at position-18 and reverse transcribed DNA using 17-mers, 18mers, or 19-mers (as primers). Generally reactivity of the viral RTs, AMV / HIV / MMLV, towards cDNA synthesis was similar for templates containing G or I as well as for those with 8-oxoG or 8-oxoI. Notable differences are: 1) the use of 18-mers of DNA (to explore cDNA synthesis past the lesion/modification) led to inhibition of DNA elongation in cases where a G:dA wobble pair was present, while the presence of I, 8-oxoI, or 8-oxoG led to full synthesis of the corresponding cDNA, with the latter two displaying a more efficient process; 2) HIV RT is more sensitive to modified base pairs in the vicinity of cDNA synthesis; and 3) the presence of a modification two positions away from transcription initiation has an adverse impact on the overall process. Steady-state kinetics were established using AMV RT to determine substrate specificities towards canonical dNTPs (N = G, C, T, A). Overall we found evidence that RNA templates containing inosine are likely to incorporate dC > dT > > dA, where reactivity in the presence of dA was found to be pH dependent (process abolished at pH 7.3); and that the absence of the C2-exocyclic amine, as displayed with templates containing 8-oxoI, leads to increased selectivity towards incorporation of dA over dC. The data will be useful in assessing the impact that the presence of inosine and/or oxidatively generated lesions have on viral processes and adds to previous reports where I codes exclusively like G. Similar results were obtained upon comparison of AMV and MMLV RTs.

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“…An oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-hydroxyguanine; 8-oxo-G), is a ubiquitous oxidative lesion, readily detectable in cellular nucleic acids [34,42]. When present in mRNA, 8-oxo-G interferes with decoding, possibly through the formation of a Hoogsteen pair with adenine when the base rotates around the N-glycosidic bond [43]. The altered base-pairing capacity of 8-oxo-G can also perturb RNA folding.…”

Section: Oxidative Modification Of Rrnamentioning

confidence: 99%

The Impact of Oxidative Stress on Ribosomes: From Injury to Regulation

Shcherbik

Pestov

2019

Cells

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The ribosome is a complex ribonucleoprotein-based molecular machine that orchestrates protein synthesis in the cell. Both ribosomal RNA and ribosomal proteins can be chemically modified by reactive oxygen species, which may alter the ribosome′s functions or cause a complete loss of functionality. The oxidative damage that ribosomes accumulate during their lifespan in a cell may lead to reduced or faulty translation and contribute to various pathologies. However, remarkably little is known about the biological consequences of oxidative damage to the ribosome. Here, we provide a concise summary of the known types of changes induced by reactive oxygen species in rRNA and ribosomal proteins and discuss the existing experimental evidence of how these modifications may affect ribosome dynamics and function. We emphasize the special role that redox-active transition metals, such as iron, play in ribosome homeostasis and stability. We also discuss the hypothesis that redox-mediated ribosome modifications may contribute to adaptive cellular responses to stress.

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Insights into the base-pairing preferences of 8-oxoguanosine on the ribosome

Cited by 23 publications

References 72 publications

Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

Translesion synthesis by AMV, HIV, and MMLVreverse transcriptases using RNA templates containing inosine, guanosine, and their 8-oxo-7,8-dihydropurine derivatives

The Impact of Oxidative Stress on Ribosomes: From Injury to Regulation

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