Source:Cell Reports
Author(s): Katya Marjon, Michael J. Cameron, Phong Quang, Michelle F. Clasquin, Everton Mandley, Kaiko Kunii, Michael McVay, Sung Choe, Andrew Kernytsky, Stefan Gross, Zenon Konteatis, Joshua Murtie, Michelle L. Blake, Jeremy Travins, Marion Dorsch, Scott A. Biller, Kevin M. Marks
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.
Graphical abstract
Teaser
Marjon et al. show that multiple synthetic lethal targets emerge in cancers with MTAP deletion. MTAP loss leads to the accumulation of its substrate, which inhibits the activity of the methyltransferase PRMT5 and sensitizes cancer cells to PRMT5 targeting. Enzymes supporting PRMT5 function, including MAT2A and PRMT5 binding partner, RIOK1, are also vulnerable.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/1qc9mtM
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