RRC ID 64934
Author Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, McVay M, Choe S, Kernytsky A, Gross S, Konteatis Z, Murtie J, Blake ML, Travins J, Dorsch M, Biller SA, Marks KM.
Title MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis.
Journal Cell Rep
Abstract Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.
Volume 15(3)
Pages 574-587
Published 2016-4-19
DOI 10.1016/j.celrep.2016.03.043
PII S2211-1247(16)30299-6
PMID 27068473
MeSH Adenosine / analogs & derivatives* Adenosine / metabolism Antigens, Neoplasm / metabolism* Gene Deletion* Genomics HCT116 Cells Humans Methionine Adenosyltransferase / metabolism* Multiprotein Complexes / metabolism Neoplasms / enzymology* Neoplasms / metabolism Protein Serine-Threonine Kinases / metabolism* Protein-Arginine N-Methyltransferases / metabolism* Purine-Nucleoside Phosphorylase / deficiency Purine-Nucleoside Phosphorylase / metabolism* RNA, Small Interfering / metabolism Signal Transduction* Thionucleosides / metabolism*
IF 8.109
Human and Animal Cells KP4(RCB1005) Lu99(RCB1900)