Abstract
We observed overexpression and increased intranuclear 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 cellmigration 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.
Original language | English |
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Pages (from-to) | 11106-11120 |
Number of pages | 15 |
Journal | Nucleic Acids Research |
Volume | 45 |
Issue number | 19 |
DOIs | |
State | Published - 2 Nov 2017 |