Dataset Information

VRK1 is required in VRK2-methylated cancers of the nervous system

ABSTRACT: 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. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout in VRK2-expressing cell lines sensitized cells to VRK1 knockout, and conversely, VRK2 overexpression increased cell fitness in VRK1-dependent cell lines upon suppression of VRK1. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas, and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced Barrier-to-Autointegration Factor (BAF) phosphorylation, induced abnormal chromosome segregation. and dysregulated nuclear membrane re-formation following mitosis, resulting in increased DNA damage and apoptosis. Together, these observations identify VRK1 as a synthetic lethal target in VRK2-methylated adult and pediatric gliomas and neuroblastomas.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Thermo Fisher Scientific Center for Multiplexed Proteomics

LAB HEAD: William Hahn

PROVIDER: PXD030599 | Pride | 2022-09-06

REPOSITORIES: Pride

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			Action	DRS
	13775_eb01428733_human_tmt16_phos_9262020.pep.xml	Pepxml
	13776_eb01430733_human_tmt16_phos_9262020.pep.xml	Pepxml
	13777_eb01431733_human_tmt16_phos_9262020.pep.xml	Pepxml
	13778_eb01432733_human_tmt16_phos_9262020.pep.xml	Pepxml
	13779_eb01433733_human_tmt16_phos_9262020.pep.xml	Pepxml

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VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system.

So Jonathan J Mabe Nathaniel W NW Englinger Bernhard B Chow Kin-Hoe KH Moyer Sydney M SM Yerrum Smitha S Trissal Maria C MC Marques Joana G JG Kwon Jason J JJ Shim Brian B Pal Sangita S Panditharatna Eshini E Quinn Thomas T Schaefer Daniel A DA Jeong Daeun D Mayhew David L DL Hwang Justin J Beroukhim Rameen R Ligon Keith L KL Stegmaier Kimberly K Filbin Mariella G MG Hahn William C WC

JCI insight 20221010 19

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens 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 in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VR ...[more]

PMID: 36040810

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