RNA Modifications in Biology
RNA modifications are prevalent, dynamic, and important for nearly every stage of an RNA’s life in the cell. We are interested in the mechanisms of chemical modifications that regulate gene expression.
The m6A modification has been shown to regulate stability, translation, splicing and transcription of mRNAs. Dysregulation of the enzymes associated with m6A has been linked to developmental disorders and diseases, including cancer. We are investigating how the m6A modification machinery selects their RNA targets for specific and controlled methylation. We aim to determine the enzymatic and regulatory mechanisms to further our understanding of aberrant methyltransferase activity in development and disease.
We also study how modifying noncoding RNAs (e.g. tRNAs) affect cellular events. For example, we have shown how certain tRNAs are stabilized by m7G modification by elucidating the cryo-EM structures of the writer enzyme with tRNA. Many chemical reactions occur on noncoding RNAs, and we aim to understand how the chemistry affects the biological functions of the RNAs.
Cryo-EM structures of the m7G writer enzyme complex (METTL1-WDR4, Ruiz-Arroyo et al. 2023) show how the proteins activate the tRNA to open for modification.
We revealed a structural explanation for how human METTL16, an m6A methyltransferase, regulates S-adenosylmethionine levels in the cell (Doxtader et al. 2018).
Autoinhibition of METTL16 by a protein loop that covers SAM binding site can tune the methylation efficiency to eventually control SAM biosynthesis and cellular metabolism.
We determined crystal structures of the human METTL3/METTL14 methyltransferase complex, a key enzyme that is responsible for most m6A modifications in mRNAs (Wang, 2016).