The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer.
We observed overexpression and increased intra-nuclear accumulation of the PRMT5/WDR77 in breast cancer cell lines relative to immortalized breast epithelial cells. Utilizing mass spectrometry and biochemistry approaches we identified the Zn-finger protein ZNF326, as a novel interaction partner and substrate of the nuclear PRMT5/WDR77 complex. ZNF326 is symmetrically dimethylated at ... arginine 175 (R175) and this modification is lost in a PRMT5 and WDR77-dependent manner. Loss of PRMT5 or WDR77 in MDA-MB-231 cells leads to defects in alternative splicing, including inclusion of A-T rich exons in target genes, a phenomenon that has previously been observed upon loss of ZNF326. We observed that the alternatively spliced transcripts of a subset of these genes, involved in proliferation and tumor cell migration like REPIN1/AP4, ST3GAL6, TRNAU1AP and PFKM are degraded upon loss of PRMT5. In summary, we have identified a novel mechanism through which the PRMT5/WDR77 complex maintains the balance between splicing and mRNA stability through methylation of ZNF326.
Mesh Terms:
Alternative Splicing, Breast Neoplasms, Carrier Proteins, Cell Line, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, MCF-7 Cells, Protein Binding, Protein-Arginine N-Methyltransferases, Reverse Transcriptase Polymerase Chain Reaction, Tandem Mass Spectrometry, Transcription Factors
Alternative Splicing, Breast Neoplasms, Carrier Proteins, Cell Line, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, MCF-7 Cells, Protein Binding, Protein-Arginine N-Methyltransferases, Reverse Transcriptase Polymerase Chain Reaction, Tandem Mass Spectrometry, Transcription Factors
Nucleic Acids Res.
Date: Nov. 02, 2017
PubMed ID: 28977470
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