Small RNAs are Big in Biology: BU Researchers Discover Unique Mechanism

Boston University researchers published a groundbreaking paper in “Molecular Cell” earlier this year, identifying a unique mechanism of guide RNA biogenesis. The paper, “Antisense Transcripts Delimit Exonucleolytic Activity of the Mitochondrial 3’ Processome to Generate Guide RNAs,” details a fundamentally novel molecular mechanism of making guide RNAs (gRNAs).

This paper was authored by a team of researchers led by Dr. Ruslan Afasizhev, Professor of Molecular and Cell Biology. The BU contributors were Dr. Takuma Suematsu, Postdoctoral Associate in the Department of Molecular and Cell Biology; Dr. Liye Zhang, Postdoctoral Fellow, and Dr. Stefano Monti, Associate Professor in the Section of Computational Biomedicine; Dr. Inna Afasizheva, Assistant Professor in the Department of Molecular and Cell Biology; Dr. Qi Wang, Postdoctoral Associate in the Department of Biochemistry; and Dr. Catherine E. Costello, Director of the Center for Biomedical Mass Spectrometry in the Department of Biochemistry. Dr. Lan Huang, from the Department of Physiology & Biophysics of the Boston University School of Medicine (BUSM) and the University of California, Irvine, also contributed to the paper.

Before the discovery of microRNA, RNA editing was described in mitochondria of unicellular human parasite Trypanosoma brucei. The protein-encoding messenger RNA molecules undergo massive sequence changes during the editing process, caused by insertion and deletion of uridine nucleotides. It was hypothesized that the RNA editing patterns were dictated by small RNAs, termed “guide RNAs,” which were discovered in the 1990s. The small RNA revolution originated in 1993 from work on roundworm Caenorhabditis elegans, which uncovered the regulatory role of microRNAs in gene expression. From this work, small RNAs emerged as the major drivers of virtually all cellular processes. However, how guide RNAs are produced in the Trypanosoma brucei parasite remained a mystery for 25 years until the collaborative work of researchers from GSDM and the School of Medicine unraveled a unique mechanism of gRNA biogenesis.

The Boston University and University of California, Irvine, researchers’ paper establishes sense and antisense transcription patterns that generate short double-stranded region and define the guide RNA length by inhibiting a specialized degradation enzyme. Along the way, the authors discovered a macromolecular protein complex containing two enzymes unique to trypanosomes. Because the entire pathway is absent in humans, therapeutic targeting of enzymes involved in guide RNA biogenesis is a promising approach to finding cures against African sleeping sickness and other neglected tropical diseases.

“Time and again, this work demonstrates the value of studies of evolutionary divergent organisms, such as flagellated human parasites,” Dr. Afasizhev said. “This research provides a sound drug target and broadens horizons of RNA biology. I expect similar mechanisms to be discovered in other systems in the near future.”