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


ABSTRACT: 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.

SUBMITTER: Fong JY 

PROVIDER: S-EPMC7194031 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Fong Jia Yi JY   Pignata Luca L   Goy Pierre-Alexis PA   Kawabata Kimihito Cojin KC   Lee Stanley Chun-Wei SC   Koh Cheryl M CM   Musiani Daniele D   Massignani Enrico E   Kotini Andriana G AG   Penson Alex A   Wun Cheng Mun CM   Shen Yudao Y   Schwarz Megan M   Low Diana Hp DH   Rialdi Alexander A   Ki Michelle M   Wollmann Heike H   Mzoughi Slim S   Gay Florence F   Thompson Christine C   Hart Timothy T   Barbash Olena O   Luciani Genna M GM   Szewczyk Magdalena M MM   Wouters Bas J BJ   Delwel Ruud R   Papapetrou Eirini P EP   Barsyte-Lovejoy Dalia D   Arrowsmith Cheryl H CH   Minden Mark D MD   Jin Jian J   Melnick Ari A   Bonaldi Tiziana T   Abdel-Wahab Omar O   Guccione Ernesto E  

Cancer cell 20190801 2


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  ...[more]

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