When genetic information is transferred from DNA to RNA and then protein, messenger RNA can be controlled in various ways. Not only does RNA need to be properly spliced, but it also requires help for initiating translation. Moreover, RNA stability is important as it determines how much protein can be translated from the RNA. A chemical modification, specifically methylation, of RNA has been shown to regulate all of these critical steps of the RNA life cycle. RNA methylation is reversible, and all of the enzymes involved--writers, readers, and erasers--have been implicated in having some role in cancer. However, because we know little about how the modification is added to the RNAs, it has be...

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When genetic information is transferred from DNA to RNA and then protein, messenger RNA can be controlled in various ways. Not only does RNA need to be properly spliced, but it also requires help for initiating translation. Moreover, RNA stability is important as it determines how much protein can be translated from the RNA. A chemical modification, specifically methylation, of RNA has been shown to regulate all of these critical steps of the RNA life cycle. RNA methylation is reversible, and all of the enzymes involved--writers, readers, and erasers--have been implicated in having some role in cancer. However, because we know little about how the modification is added to the RNAs, it has been difficult to dissect how alteration of the RNA modification machinery might lead to disease. We have been working on the molecular details of the enzymes that add a methyl group to RNAs, including determining three-dimensional structures at atomic resolution. Guided by a physical model, we propose to use various mutations of the RNA modifiers (METTL3, METTL14, WTAP), to understand how they interact and find RNAs to modify. We will then use the same mutations to correlate the biochemical effects to how they affect gene expression and cell growth, in order to derive a model for how RNA methylation affects tumor formation. In addition, we will search for small drug-like molecules that can interfere with RNA modification, as a search for potential therapeutic agents against cancer.

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