# Nutrient stress diverts RRN3 from rRNA transcription to alternative polyadenylation of autophagy mRNAs in ovarian cancer

## TL;DR

This study shows how a protein called RRN3 helps ovarian cancer cells survive under stress by switching from making rRNA to regulating mRNA stability, promoting cancer growth.

## Contribution

The study reveals a novel role for RRN3 in stress-induced mRNA processing and autophagy regulation in ovarian cancer.

## Key findings

- RRN3 regulates alternative polyadenylation (APA) of autophagy-related mRNAs under nutrient stress.
- Phosphorylation of RRN3 at serine 199 redirects it from the nucleolus to regulate APA, enhancing mRNA stability.
- The RRN3 switch from rRNA transcription to APA regulation is crucial for ovarian cancer progression in mice.

## Abstract

Stress-induced alternative processing of mRNA is emerging as an essential mechanism to drive almost every hallmark of cancer. Through a genome-wide screening based on an abnormal transcriptional readthrough event favoring the malignant progression of ovarian carcinoma (OC), we identified novel mRNA processing regulators including RRN3, an essential factor for the transcriptional initiation of rRNA. The long-read RNA sequencing and PAR-CLIP analyses revealed that RRN3 was involved in the usage of alternative polyadenylation (APA) sites, resulting in the altered stability of autophagy-related mRNAs. More interestingly, we discovered that nutrient-deprivation-induced phosphorylation of RRN3 at serine 199 was sufficient to divert RRN3 out of the nucleolus to the nuclear plasma, where RRN3 regulated the APA of autophagy mRNAs, such as OPTN, to enhance their stability and eventually promoted autophagy. Further in vivo experiments showed that nutrient-stress-triggered switch of RRN3 from rRNA transcription to APA regulation was essential for the growth and dissemination of OC in mice.