Oncotarget

Research Papers:

RBR-type E3 ubiquitin ligase RNF144A targets PARP1 for ubiquitin-dependent degradation and regulates PARP inhibitor sensitivity in breast cancer cells

Ye Zhang, Xiao-Hong Liao, Hong-Yan Xie, Zhi-Min Shao _ and Da-Qiang Li

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Oncotarget. 2017; 8:94505-94518. https://doi.org/10.18632/oncotarget.21784

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Abstract

Ye Zhang1,*, Xiao-Hong Liao1,2,3,*, Hong-Yan Xie1,2,3, Zhi-Min Shao1,2,3,4,5 and Da-Qiang Li1,2,3,4,5

1Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China

2Department of Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China

3Cancer Institute, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China

4Department of Breast Surgery, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China

5Key Laboratory of Breast Cancer in Shanghai, Shanghai Medical College, Fudan University, Shanghai 200032, China

*These authors have contributed equally to this work

Correspondence to:

Zhi-Min Shao, email: zhimingshao@yahoo.com

Da-Qiang Li, email: daqiangli1974@fudan.edu.cn

Keywords: breast cancer, PARP1, E3 ubiquitin-protein ligase, ubiquitination, proteasomal degradation

Received: August 08, 2017     Accepted: September 23, 2017     Published: October 10, 2017

ABSTRACT

Poly(ADP-ribose) polymerase 1 (PARP1), a critical DNA repair protein, is frequently upregulated in breast tumors with a key role in breast cancer progression. Consequently, PARP inhibitors have emerged as promising therapeutics for breast cancers with DNA repair deficiencies. However, relatively little is known about the regulatory mechanism of PARP1 expression and the determinants of PARP inhibitor sensitivity in breast cancer cells. Here, we report that ring finger protein 144A (RNF144A), a RING-between-RING (RBR)-type E3 ubiquitin ligase with an unexplored functional role in human cancers, interacts with PARP1 through its carboxy-terminal region containing the transmembrane domain, and targets PARP1 for ubiquitination and subsequent proteasomal degradation. Moreover, induced expression of RNF144A decreases PARP1 protein levels and renders breast cancer cells resistant to the clinical-grade PARP inhibitor olaparib. Conversely, knockdown of endogenous RNF144A increases PARP1 protein levels and enhances cellular sensitivity to olaparib. Together, these findings define RNF144A as a novel regulator of PARP1 protein abundance and a potential determinant of PARP inhibitor sensitivity in breast cancer cells, which may eventually guide the optimal use of PARP inhibitors in the clinic.


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