The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer

Madhumitha Rengasamy, Fan Zhang, Ajay Vashisht, Won Min Song, Francesca Aguilo, Yifei Sun, Si De Li, Weijia Zhang, Bin Zhang, James A. Wohlschlegel, Martin J. Walsh

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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 languageEnglish
Pages (from-to)11106-11120
Number of pages15
JournalNucleic Acids Research
Volume45
Issue number19
DOIs
StatePublished - 2 Nov 2017

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