ZO-1 and ZONAB Interact to Regulate Proximal Tubular Cell Differentiation

Abstract

<h3>Abstract</h3> Collateral lethality occurs when loss of one paralog renders cancer cells dependent on the remaining paralog. Combining genome scale CRISPR/Cas9 screens coupled with RNA-sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase Vaccinia-Related Kinase 1 (VRK1) for their survival. <i>VRK1</i> dependency was inversely correlated with expression of its paralog VRK2. <i>VRK2</i> knockout (KO) sensitized cells to <i>VRK1</i> suppression, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 suppression. DNA methylation of the <i>VRK2</i> promoter was associated with low VRK2 expression in human neuroblastomas, and adult and pediatric gliomas. Mechanistically, depletion of <i>VRK1</i> reduced Barrier-to-Autointegration Factor (BAF) phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in <i>VRK2</i> promoter-methylated adult and pediatric gliomas and neuroblastomas. <h3>Statement of Significance</h3> We credential VRK1 as a target in adult and pediatric gliomas, and neuroblastomas with <i>VRK2</i> promoter methylation. This demonstrates the utility of paralog-driven synthetic lethal interactions for biomarker-linked, targeted therapeutics.