DCAF13-mediated K63-linked ubiquitination of RNA polymerase I promotes uncontrolled proliferation in Breast Cancer

Zhi-Zhi Yang, Bing Yang, Haiyan Yan, Xingyu Ma, Bin Tian, Bingqi Zheng, Yong-Xian Chen, Yi-Ming Dong, Jinsi Deng, Ziling Zhan, Yanmei Shi, Jing Yuan Zhang, Daning Lu, Jie-Hua He, Yin Zhang, KaiShun Hu, Shuang Zhu, Keda Zhou, Yu-Chan Zhang, Yiqing Zheng (), Dong Yin () and Jian-You Liao ()
Additional contact information
Zhi-Zhi Yang: Sun Yat-sen University
Bing Yang: Sun Yat-sen University
Haiyan Yan: Sun Yat-sen University
Xingyu Ma: Sun Yat-sen University
Bin Tian: Sun Yat-sen University
Bingqi Zheng: Sun Yat-sen University
Yong-Xian Chen: Sun Yat-sen University
Yi-Ming Dong: Sun Yat-sen University
Jinsi Deng: Sun Yat-sen University
Ziling Zhan: Sun Yat-sen University
Yanmei Shi: Sun Yat-sen University
Jing Yuan Zhang: Sun Yat-sen University
Daning Lu: Sun Yat-sen University
Jie-Hua He: Sun Yat-sen University
Yin Zhang: Sun Yat-sen University
KaiShun Hu: Sun Yat-sen University
Shuang Zhu: Guangdong Pharmaceutical University
Keda Zhou: the University of Hong Kong
Yu-Chan Zhang: Sun Yat-Sen University
Yiqing Zheng: Sun Yat-sen University
Dong Yin: Sun Yat-sen University
Jian-You Liao: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Hyperactivation of ribosome biogenesis (RiBi) drives cancer progression, yet the role of RiBi-associated proteins (RiBPs) in breast cancer (BC) is underexplored. In this study, we perform a comprehensive multi-omics analysis and reveal that assembly and maturation factors (AMFs), a subclass of RiBPs, are upregulated at both RNA and protein levels in BC, correlating with poor patient outcomes. In contrast, ribosomal proteins (RPs) do not show systematic upregulation across various cancers, including BC. We further demonstrate that the oncogenic activation of a top AMF candidate in BC, DCAF13, enhances Pol I transcription and promotes proliferation in BC cells both in vitro and in vivo. Mechanistically, DCAF13 promotes Pol I transcription activity by facilitating the K63-linked ubiquitination of RPA194. This process stimulates global protein synthesis and cell growth. Our findings uncover a modification of RPA194 that regulates Pol I activity; this modification is dysregulated in BC, contributing to cancer progression.

Date: 2025
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DOI: 10.1038/s41467-025-55851-9

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