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RNA strands are far more important structural and control elements in the cell than previously thought / 537 unknown RNA-protein compounds discovered thanks to newly established method / Method can help to identify new therapeutic approaches for cancer

For decades, RNA molecules were regarded almost exclusively as mobile transcripts of genetic material in the cell. Scientists at the Freiburg University Medical Center and the German Cancer Research Center have now used a newly developed method to show that the thread-like molecules are far more involved in cellular processes than previously thought. Using this method, they identified all proteins that bind RNA molecules or are directly dependent on such proteins. They found 537 previously unknown compounds, which the researchers now want to investigate in more detail. They hope to gain a better understanding of RNA functions and find new targets for cancer drugs. The researchers present their methods and results in a study in the journal Molecular Cell , which was published online in advance on May 7, 2019.

"We have succeeded in deciphering a previously largely unknown network of interactions in the cell. This offers us opportunities to look for new therapeutic approaches for diseases such as cancer," says study leader Prof. Dr. Sven Diederichs, Head of the Department of Oncological Research at the Department of Thoracic Surgery at the Freiburg University Medical Center and Head of the Department of RNA Biology and Cancer at the German Cancer Research Center (DKFZ).

RNA is a blueprint, component and control element in one

It has been known for decades that so-called messenger RNA (mRNA) is formed in the cell nucleus as a transcript of DNA and is translated into the language of proteins outside the nucleus. In the last ten years, however, researchers worldwide, including Prof. Diederichs and his team, have discovered that RNAs have many other functions. "We now know that RNA can bind directly to proteins and thus influence their activity and function," says Prof. Diederichs.

Using the new method known as R-DeeP, the researchers have now succeeded in identifying all the proteins in a tumor cell that are directly or indirectly dependent on RNA binding. It also makes it possible to investigate the structure and function of RNA-dependent protein complexes in great detail. "We already know that many RNA molecules are incorrectly regulated in cancer cells. By deciphering molecular complexes and signaling pathways in tumor cells with R-DeeP, we can better understand the consequences for tumor growth," says Prof. Diederichs. It is also possible to quantitatively determine what percentage of a certain type of protein actually binds RNA. This reveals whether a protein is strongly or only weakly RNA-dependent.

For some years now, intensive research has also been carried out into drugs that either use RNA as a therapeutic agent or vaccine or that specifically switch off RNA molecules. So far, this approach has mainly targeted viral diseases such as hepatitis C or neurological diseases. "However, this approach could also be used for cancer therapy," says Prof. Diederichs. However, before this is possible, the researchers still need to conduct more intensive research into RNA-mediated basic functions and processes in the cell.

Original title of the study: R-DeeP: Proteome-wide and Quantitative Identification of RNA-dependent Proteins by Density Gradient Ultracentrifugation

DOI: 10.1016/j.molcel.2019.04.018

Link: www.cell.com/molecular-cell/fulltext/S1097-2765(19)30310-7

Contact: 
Prof. Dr. Sven Diederichs 
Head of the Department of Oncological Research 
Department of Thoracic Surgery 
Freiburg University Medical Center 
Phone: 0761 270-77571 
sven.diederichs@uniklinik-freiburg.de

and

Head of the Department of RNA Biology and Cancer 
German Cancer Research Center (DKFZ) Heidelberg