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PRMT5 regulates ATF4 transcript splicing and oxidative stress response.
Szewczyk, Magdalena M; Luciani, Genna M; Vu, Victoria; Murison, Alex; Dilworth, David; Barghout, Samir H; Lupien, Mathieu; Arrowsmith, Cheryl H; Minden, Mark D; Barsyte-Lovejoy, Dalia.
Afiliación
  • Szewczyk MM; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Luciani GM; Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Vu V; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Ontario, Canada.
  • Murison A; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Dilworth D; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Barghout SH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • Lupien M; Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
  • Minden MD; Department of Medical Biophysics, University of Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address: Mark.Minden@uhn.ca.
  • Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. Electronic address: d.barsyte@utoronto.ca.
Redox Biol ; 51: 102282, 2022 05.
Article en En | MEDLINE | ID: mdl-35305370
Protein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Leucemia Mieloide Aguda Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Redox Biol Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Leucemia Mieloide Aguda Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Redox Biol Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos