PXD030599

PXD030599 is an original dataset announced via ProteomeXchange.

Title	VRK1 is required in VRK2-methylated cancers of the nervous system
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-09-06
AnnouncementXML	Submission_2022-09-05_17:35:36.283.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thermo Fisher Scientific Center for Multiplexed Proteomics
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-22 02:42:58	ID requested
⏵ 1	2022-09-05 17:35:37	announced

So J, Mabe NW, Englinger B, Chow KH, Moyer SM, Yerrum S, Trissal MC, Marques JG, Kwon JJ, Shim B, Pal S, Panditharatna E, Quinn T, Schaefer DA, Jeong D, Mayhew DL, Hwang J, Beroukhim R, Ligon KL, Stegmaier K, Filbin MG, Hahn WC, VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system. JCI Insight, 7(19):(2022) [pubmed]

submitter keyword: phosphorylation

William Hahn
contact affiliation	Dana-Farber Cancer Institute
contact email	william_hahn@dfci.harvard.edu
lab head
Thermo Fisher Scientific Center for Multiplexed Proteomics
contact affiliation	Harvard Medical School
contact email	tcmp@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030599
     1. Label: PRIDE project
     2. Name: VRK1 is required in VRK2-methylated cancers of the nervous system