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

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.

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Publication Details

Journal
Cell Death and Disease
Published
2025-11-21
DOI
https://doi.org/10.1038/s41419-025-08142-6
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Yi Shi, Rong Xiang, Jiaji Ding, Beilei Zeng et al.
Cell Death and Disease
RNA Research and Splicing
article

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

Yi Shi, Rong Xiang, Jiaji Ding, Beilei Zeng, Tianxiang Liu, Jianying Lv, Yanhua Liu, Yi Liu, Shuo Wang, Jian Li, Zhiqiang Chen, Jia Li, Longlong Wang, Yuting Bai, Wei Ding, Wang Qu, Yongjun Piao, Yanan Chen
article en

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.

Cell Death and DiseaseVol. 16(1)
North Sichuan Medical University (CN), Nankai University (CN), Tianjin First Center Hospital (CN), Affiliated Hospital of North Sichuan Medical College (CN), Tianjin Central Hospital of Gynecology Obstetrics (CN), Tianjin Medical University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Inner Mongolia, Nankai University, Natural Science Foundation of Tianjin City
Openalex Percentile: Top 68%
RNA Research and Splicing
DOIOpen Access PDFOpenAlex
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