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Breaking the RNA capping paradigm

Published on October 13, 2020

This discovery by a team of IRIC researchers could soon be taught in molecular biology courses. Katherine Borden’s laboratory recently published a study in the journal PNAS that demonstrated that the activity of RNAs can be regulated in a new way: by modulating a RNA modification known as capping. The paradigm in molecular biology is that all mRNAs, and many non-coding RNAs, are constitutively capped.  The team showed that this is not the case, with many RNAs only 30-50% capped at steady state. The team discovered that eIF4E, a protein involved in cancer, unexpectedly modulates capping of RNAs. In turn, modifies their activity acting as downstream purveyors of eIF4E’s oncogenic activity.

If one of the main functions of a gene is to provide a protein, it is first copied into so-called “messenger” RNA, which can itself undergo various modifications. One such modification is the addition of a cap, consisting of a methylated guanosine group, to the messenger RNA. Capping is considered a housekeeping activity which means a constitutive modification. This cap is important for coding RNAs, for the conversion of messenger RNA into its active protein form and for the activity of non-coding RNAs. The team found that capping is instead a regulatable feature and thus provides a novel control point for the cells.  As an example, the team showed that the oncoprotein eIF4E modulates the capping and thus activities of many RNAs which likely act as downstream effectors of its activity. These exciting new findings are based on new methods developed by Dr Biljana Culjkovic-Kraljacic, to quantify the amount of cap added to RNAs. These tools have led to some unexpected observations.

As eIF4E is involved in the development of malignant tumours, the authors investigated and showed for the first time that capping of specific RNAs was highly elevated in primary cancer specimens. For the first time, the step of adding the cap has been highlighted as an essential process in the regulation of RNAs – many of which are known to be involved in cancer.

 

Referenced study

The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and non-coding transcripts. PNAS. Biljana Culjkovic-Kraljacic, Lucy A. Skrabanek, Maria V. Revuelta, Jadwiga Gasiorek, Victoria H. Cowling, Leandro Cerchietti, Katherine L.B. Borden

https://www.pnas.org/content/early/2020/10/13/2002360117