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Publication : Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

First Author  Fong JY Year  2019
Journal  Cancer Cell Volume  36
Issue  2 Pages  194-209.e9
PubMed ID  31408619 Mgi Jnum  J:278930
Mgi Id  MGI:6359485 Doi  10.1016/j.ccell.2019.07.003
Citation  Fong JY, et al. (2019) Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell 36(2):194-209.e9
abstractText  Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
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