Editors' ChoiceCancer

New connections: Targeting PRMTs in cancer

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Science Signaling  27 Aug 2019:
Vol. 12, Issue 596, eaaz1991
DOI: 10.1126/scisignal.aaz1991

Drugs that block protein methyltransferases may be effective in RNA splicing–mutant cancers.

The posttranslational modification of proteins regulates their stability, localization, and activity. Perhaps the most widely studied and understood modification is phosphorylation (and the reciprocal dephosphorylation). Less well understood, at least beyond its role on histones in gene expression, is protein methylation. The protein arginine methyltransferase (PRMT) enzyme PRMT5 methylates arginine residues in target proteins to modify their function. PRMT5 functions in various cellular processes and is implicated in cancer. In the Science Signaling archives, Musiani et al. used new proteomic methods to explore the substrate specificity of PRMT5. Their study revealed that PRMT5 appeared to have a preferred target site—a glycine-sandwiched arginine, or “GRG” sequence—and identified previously unknown substrates of the enzyme, most abundantly proteins that regulate RNA processing, metabolism, and splicing. Now, a study from some of the same authors with additional collaborators demonstrates how this information may be put to use for cancer patients. PRMT inhibitors have shown efficacy in various cancers, but how and why they work, and which patients might benefit most, was not always understood. Following on from the findings in Musiani et al., Fong and colleagues found that PRMT5 inhibitors combined with a type I PRMT inhibitor preferentially killed acute myeloid leukemia cells that express RNA splicing factor mutants and markedly improved survival in mice implanted with these cells. These splicing mutants are found in other types of cancers, including solid tumors, but such RNA-binding proteins are challenging to target. These findings suggest that PRMT inhibitors may provide an alternative way to target them and be more widely effective beyond this subset of leukemia.

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