# PRMT1 oligomerization regulates RNA-binding protein cascade to promote pancreatic cancer

## TL;DR

This study shows that PRMT1 forms oligomers that help it regulate RNA metabolism and promote pancreatic cancer growth.

## Contribution

The study reveals the cryo-EM structure of human PRMT1 oligomers and their role in PDAC tumor growth.

## Key findings

- PRMT1 oligomerization enhances its binding and activity with RGG motif substrates.
- Disrupting PRMT1 oligomerization reduces arginine methylation and inhibits PDAC tumor growth.
- PRMT1 oligomers, not just dimers, are critical for PDAC progression.

## Abstract

This study reveals that PRMT1 forms functional helical oligomers that enhance substrate binding and activity, with implications for cancer cell proliferation and RNA metabolism.

PRMT1 is the predominant type I protein arginine methyltransferase responsible for generating monomethylarginine and asymmetric dimethylarginine (MMA and ADMA) in various protein substrates. It regulates numerous biological processes, including RNA metabolism, mRNA splicing, DNA damage repair, and chromatin dynamics. The crystal structure of rat PRMT1 has been previously reported as a homodimer; however, higher-order oligomeric species of human PRMT1 have been observed in vivo, and their structural basis remains elusive. In this study, we present the cryo-EM structure of human PRMT1 in its oligomeric form, revealing novel interfaces crucial for PRMT1 self-assembly and normal function. PRMT1 shows a strong preference for intrinsically disordered RGG/RG motifs, which are commonly found in RNA-binding proteins, highlighting its critical role in regulating RNA metabolism. In vitro studies indicate that disrupting PRMT1 oligomerization impairs its binding affinity for RGG motif substrates, thereby reducing arginine methylation levels on these substrates. This finding emphasizes the essential role of the oligomeric state of PRMT1 in its function with RGG motif-containing RNA-binding proteins. In vivo, the loss of PRMT1 oligomerization leads to decreased global ADMA levels in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits PDAC tumor growth. Collectively, we propose that PRMT1 oligomerization, rather than mere dimerization, is sufficient for PRMT1-driven PDAC tumor growth, offering novel insights into the potential therapeutic targeting of PRMT1 oligomeric forms in PDAC.