2. Academic Validation
  3. Stabilization of AFF1 by PARylation ensures transcriptional restart after DNA damage

Stabilization of AFF1 by PARylation ensures transcriptional restart after DNA damage

  • Nat Chem Biol. 2025 Oct 8. doi: 10.1038/s41589-025-02045-5.
Feifeng Zhu # 1 2 3,  Huanyi Fu # 2 4,  Wenxuan Zhu # 2,  Chengyu Li # 2,  Min Yang 2,  Zeming Feng 2,  Yangqing Shao 2,  Zhuo Li 2,  Yafei Guo 1 3,  Mengting Huang 1 3,  Yitong Zhang 2,  Yaohui He 1,  Yi Lu 5,  Zhibing Wu 6,  Qiang Zhou 4,  Huipeng Jiao 2,  Jun Huang 2 7,  Long Zhang 2 7,  Yuhua Xue 8 9,  Huasong Lu 10 11
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Affiliated Xiamen Eye Center & Xiang'an Hospital, Xiamen University, Xiamen, China.
  • 2 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 3 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, China.
  • 4 School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong, China.
  • 5 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 6 Department of Oncology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 8 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Affiliated Xiamen Eye Center & Xiang'an Hospital, Xiamen University, Xiamen, China. xueyuhua@xmu.edu.cn.
  • 9 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, China. xueyuhua@xmu.edu.cn.
  • 10 Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. huasong_lu@zju.edu.cn.
  • 11 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, China. huasong_lu@zju.edu.cn.
  • # Contributed equally.
PMID: 41062835 DOI: 10.1038/s41589-025-02045-5
Abstract

Precise control of transcription is essential for cell survival under stress conditions, including DNA damage. While mechanisms of DNA damage-induced transcriptional silencing are well characterized, how transcription resumes remains less understood. Here we identify a new role for poly(ADP-ribose) polymerase 1 (PARP1) in transcriptional restart during the DNA damage response (DDR) through a mechanism termed poly(ADP-ribose)-mediated stabilization (PARSTA) of AFF1. Upon DNA damage, PARP1 binds to and PARylates AFF1 in a region targeted by the E3 Ligase Siah1, preventing AFF1 ubiquitination and promoting its stability. This stabilization supports efficient transcriptional recovery after DNA damage. Notably, cells resistant to genotoxic stress exhibit elevated PARP1 activity and AFF1 levels, while AFF1 depletion impairs DNA repair and survival. Together, these findings expand PARP1's role to the transcriptional recovery phase in DDR and suggest that targeting the PARSTA pathway may offer therapeutic potential in diseases characterized by hyperactive PARP1 and elevated levels of AFF1.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-139156
    99.86%, PARP1 Degrader