TY - JOUR
T1 - The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer
AU - Rengasamy, Madhumitha
AU - Zhang, Fan
AU - Vashisht, Ajay
AU - Song, Won Min
AU - Aguilo, Francesca
AU - Sun, Yifei
AU - Li, Si De
AU - Zhang, Weijia
AU - Zhang, Bin
AU - Wohlschlegel, James A.
AU - Walsh, Martin J.
N1 - Funding Information:
Ellison Medical Foundation Senior Scholar Award in Aging [AG-SS-2482–10 to M.J.W.]; National Institutes of Health [5RO1HL103967, 5RO1CA154903, to M.J.W., 5RO1GM089778 to J.A.W.]. Funding for open access charge: NIH. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85037973794&partnerID=8YFLogxK
U2 - 10.1093/nar/gkx727
DO - 10.1093/nar/gkx727
M3 - Article
C2 - 28977470
AN - SCOPUS:85037973794
VL - 45
SP - 11106
EP - 11120
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 19
ER -