Previously Unknown Protein Reveals RNA Repair Mechanism in Humans

Ribonucleic acids (RNAs) are single-stranded molecules that are found in all living organisms’ cells. As “transcripts” of human genes, mRNAs, for instance, play a role in the translation of genetic information by bearing the instructions for the production of a protein in their own sequence.

In order to fulfill their diverse functions in the cell, RNAs often need to be chemically modified after their creation or repaired after damage.”

Andreas Marx, Professor, Organic and Cellular Chemistry, University of Konstanz

The three-step joining (ligation) of two RNA strands at their opposing ends is one chemical reaction that plays a part here. This reaction is induced by specialized enzymes known as RNA ligases and is found in all forms of life, including fungi, viruses, and plants.

Such RNA ligases had yet to be discovered in vertebrates, including humans. The protein C12orf29, identified by an interdisciplinary research team from Konstanz, is the first human RNA ligase of this sort. The findings, at the cellular level show that the enzyme has a protective function against cellular stress.

The study was published in Nature Communications.

Antioxidant Defence System of Human Cells

We noticed C12orf29 during extensive studies of human lung carcinoma and kidney cells that we performed in search of proteins with a specific chemical signature and for which we used new chemical tools. It caught our attention because until then it was not understood what the protein's functions were.”

Andreas Marx, Professor, Organic and Cellular Chemistry, University of Konstanz

As a result, the researchers devised and applied multiple methods to purify and estimate the structure of the unknown protein, as well as conduct experiments to determine its chemical function. They were able to prove what was previously simply a plausible suspicion: C12orf29 uses adenosine triphosphate (ATP) to connect RNA strands.

The investigators were able to demonstrate in detail that this process follows a distinct three-step reaction pattern known from other life forms’ RNA ligases. After understanding the chemical mechanism, the researchers moved one step further to learn more about C12orf29’s cellular role.

We used the CRISPR/Cas gene scissors to generate a line of human kidney cells in which the gene encoding C12orf29 was knocked out. We were then able to compare these knockout (KO) cells with 'normal' kidney cells under varying experimental conditions.”

Andreas Marx, Professor, Organic and Cellular Chemistry, University of Konstanz

Particularly, when cells were treated with menadione, a K vitamin, obvious differences were noticed between KO cells and the wild-type cells with functional RNA ligase: Menadione at relatively low doses was enough to harm KO cells.

The wild-type cells, on the other hand, were only harmed in substantially greater quantities. Because menadione has been shown to generate oxidative stress, the researchers concluded that C12orf29 guards against oxidative cellular stress.

We assume that a previously hidden human RNA repair mechanism underlies this biological function of C12orf29. We now need to examine this mechanism in further studies,” Marx concluded.

Journal reference:

Yuan, Y., et al. (2023). Chemoproteomic discovery of a human RNA ligase. Nature Communications.


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