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Coenzyme- and metabolite-linked RNAs as a new paradigm in epitranscriptomics

Project description

Nucleotide moiety in coenzymes and metabolites enables new level of RNA regulation

A recent discovery in RNA biology shows that redox coenzyme nicotinamide adenine dinucleotide (NAD) attaches to bacterial RNAs in a cap-like manner and modulates the functions of these RNAs and the presence of the enzymes that synthesise or break down NAD-RNAs. The EU-funded RNACoenzyme project aims to test the hypothesis that nucleotide moiety in coenzymes and metabolites enables cells to incorporate these compounds into specific RNAs. Linking reactive moieties to RNA may provide a biological strategy to localise them to enzymes, receptors, membranes or compartments, or to modulate the turnover or function of the RNAs or their targets. This study will provide fundamentally new links between gene regulation and metabolism and uncover a new field of epitranscriptomic information.

Objective

Background: RNA is an important regulator in biology. Recently we discovered the ubiquitous redox coenzyme nicotinamide adenine dinucleotide (NAD) to be attached to bacterial RNAs in a cap-like manner, and to modulate the functions of these RNAs, and others identified NAD-RNAs in eukaryotes. Enzymes were discovered that synthesize or break down NAD-RNAs.

Scientific problems: NAD is just one of many coenzymes and metabolic intermediates that carry a nucleotide moiety which is not involved in the catalyzed reaction. Yet, it has been conserved through evolution, a fact that suggests high functional relevance.

Hypothesis: The nucleotide moiety in coenzymes and metabolites is there for a reason: It enables cells to incorporate these compounds into specific RNAs. Linking reactive organic moieties to RNA may provide a biological strategy to localize these RNAs to enzymes, receptors, membranes or compartments, to sense environmental parameters, or to modulate the turnover or function of the RNAs or their targets.

Objectives & research program: The aim of this project is to establish the scope and biological significance of coenzyme-linked RNAs in biology. We will expand the NAD captureSeq protocol to include reduced, phosphorylated, deamidated, and depyridinated NAD-RNAs. We will develop new CoenzymeSeq methods to identify cellular RNAs modified with coenzyme A, flavin, thiamine, and N-acetylglucosamine. We will apply these protocols to RNAs isolated from different organisms to explore the occurrence, abundance, and structural variety of such RNAs. For selected modified RNAs, we will unravel the biological significance and biosynthesis.

Impact: This research challenges established textbook wisdom. It will provide fundamentally new links between gene regulation and metabolism in present-day biology and uncover a new layer of epitrancriptomic information. In addition, this project will impact our basic views on the evolution of metabolism and enzymatic catalysis.

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Topic(s)

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Funding Scheme

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ERC-ADG - Advanced Grant

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Call for proposal

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(opens in new window) ERC-2019-ADG

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Host institution

RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 500 000,00
Address
SEMINARSTRASSE 2
69117 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 500 000,00

Beneficiaries (1)

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