The JAK2-V617F Mutation Destabilizes a Programmed -1 Ribosomal Frameshift Signal

Abstract

Programmed -1 ribosomal frameshifting (-1 PRF) is a translational recoding mechanism in which cis-acting elements direct elongating ribosomes to slip in the 5’ direction on mRNAs by one base. -1 PRF activity is able to downregulate gene expression by directing elongating ribosomes to premature termination codons, activating the nonsense-mediated decay pathway (NMD) and mRNA degradation. Computational methods developed by our lab identified a -1 PRF signal within the Janus Kinase 2 (JAK2) mRNA, which encodes a tyrosine kinase involved in cell proliferation, survival, and apoptosis. Here, we characterize the JAK2 -1 PRF signal. In addition, we show that the JAK2-V617F mutation, closely linked to myeloproliferative neoplasms (MPN), decreases JAK2 mediated frameshifting. This may contribute to the observed increase of JAK2 mRNA levels in MPN patient microarray and RNAseq data. Because it has been established that elevated expression levels of JAK proteins are sufficient to transform cells in vitro, our findings suggest that this may contribute to the observed increase in JAK2 kinase activity in mutant cells and thus the transforming activity of the V617F mutation. Our study offers a possible translational-level mechanism behind the development of MPNs, opening the door to new therapies for MPN patients.