Deacetylated PCBP1 licenses PARP1 activity for DNA damage repair

Yuxin Shu; Jun Zhang; Linmin Zhou; Tingting Feng; Feng Chen; Huangqi Tang; Mengyan Li; Jinqin Qian; Mengzhu Qin; Zixiang Wang; Xiaopeng Lu; Xingkai He; Longjiang Di; Jinbo Huang; Qian Zhu; Yuan Tian; Wei-Guo Zhu

doi:10.1016/j.molcel.2026.05.008

Deacetylated PCBP1 licenses PARP1 activity for DNA damage repair

Mol Cell. 2026 Jun 1:S1097-2765(26)00314-X. doi: 10.1016/j.molcel.2026.05.008. Online ahead of print.

Authors

Yuxin Shu¹, Jun Zhang², Linmin Zhou², Tingting Feng², Feng Chen², Huangqi Tang², Mengyan Li², Jinqin Qian³, Mengzhu Qin², Zixiang Wang², Xiaopeng Lu², Xingkai He², Longjiang Di², Jinbo Huang², Qian Zhu², Yuan Tian⁴, Wei-Guo Zhu⁵

Affiliations

¹ International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; School of Basic Medical Sciences, Wannan Medical University, Wuhu 241003, China.
² International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China.
³ Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center of China, Beijing 100034, China.
⁴ International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China. Electronic address: tianyuan1020@szu.edu.cn.
⁵ International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; School of Basic Medical Sciences, Wannan Medical University, Wuhu 241003, China. Electronic address: zhuweiguo@szu.edu.cn.

PMID: 42225061
DOI: 10.1016/j.molcel.2026.05.008

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor and one of the initiating enzymes essential for DNA repair. Understanding how to control PARP1 activity is critical for developing strategies to maintain genome stability. Here, we report that the RNA-binding protein poly(rC)-binding protein 1 (PCBP1) interacts with and inhibits PARP1 activity under physiological conditions, and that this inhibition is relieved in the early phase of the DNA damage response. Mechanistically, histone deacetylase SIRT7 mediates the deacetylation of PCBP1 at K314 and K351, disrupting its interaction with the DNA-binding domain of PARP1 and thereby permitting PARP1 activation. Modulating PCBP1 expression or acetylation through gene editing or antagonistic peptides affects the efficiency of DNA damage repair in both cell and murine models. Reduced PCBP1 levels are associated with poor survival in cancer patients following radiotherapy. This regulatory role for PCBP1 in PARP1 activity may form the basis of a therapeutic strategy that combines the inhibition of PCBP1 deacetylation with DNA-damaging agents.

Keywords: DNA double-strand break repair; PARP1; PARylation; PCBP1; SIRT7.