3006 – JAK2 PHOSPHORYLATES THE RNA PROCESSING PROTEIN HNRNPA1 TO REPRESS THE EXPRESSION OF RETROTRANSPOSONS AND PROTECT THE HAEMATOPOIETIC STEM CELL GENOME

The JAK2 kinase phosphorylates tyrosines on key signalling proteins upon the activation of cytokine receptors, and is therefore an essential component of the cytokine signalling pathways that control haematopoietic stem cells (HSCs) and progenitors. Retrotransposons are genetic elements that copy and reinsert themselves into the host genome via an RNA intermediate, and make up a large proportion of mammalian genomes. The repression of retrotransposon expression is critical in stem cell populations, to prevent the accumulation of detrimental mutations by insertional mutagenesis. Using proteomic and phosphoproteomic screening techniques, we demonstrate that the RNA processing protein HNRNPA1 is a novel substrate of JAK2 in haematopoietic cells. HNRNPA1 phosphomutant cell lines and mice showed that loss of JAK2-mediated tyrosine phosphorylation on HNRNPA1 alters its binding to retrotransposon RNA, and results in the accumulation of retrotransposon RNA in the cells. Our data reveal that retrotransposon sequences have evolved to interact with HNRNPA1 to increase the expression of their RNA intermediates. Phosphorylation of HNRNPA1 by JAK2 in HSCs in response to cytokines disrupts this interaction, and represses retrotransposon expression. This novel mechanism of retrotransposon repression by JAK2 and HNRNPA1 protects the HSC genome from insertional mutagenesis, and may also protect the genome in other stem cell populations.