Protein arginine methyltransferase 5 mediates the increase in interferon stimulated genes during replication stress

Replication stress (RS) is a hallmark of cancer and is defined as the perturbation of DNA replication that results in stalled or collapsed DNA replication forks. Chemotherapeutic drugs exploit this phenomenon by enhancing the RS, resulting in cell death. Protein arginine methyltransferase 5 (PRMT5) is responsible for post-translational symmetric dimethylarginine (SDMA) modification. This modification is important for regulating RS. PRMT5 is upregulated in several malignancies and therefore inhibitors have been developed. To understand the consequences of PRMT5 inhibition, we investigated its role in replication stress response. Employing the RS inducer hydroxyurea (HU) and the PRMT5 inhibitor GSK591, we discovered a PRMT5-mediated increase in SDMA during RS. Furthermore, we observed that RS resulted in a PRMT5-dependent transcriptional increase in interferon-stimulated genes (ISGs). Therefore, we demonstrated a previously unreported role for PRMT5-mediated SDMA in the context of RS.