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Peer-reviewedCC BY-NC 4.0Nucleic Acids Research

CPSF6 maintains genomic stability by stabilizing RAD52 and promoting CHK1 activation

  • Honglin Wu1,2,3
  • Hui Fu4,5,6
  • Zhenzhen Fan4,5
  • Junying Qin4,5
  • Yifei Gong3,4,5
  • Hui Zheng4,5
  • Ruiyuan An4,5
  • Xiuxiu Miao3,4,5
  • Tie-Shan Tang1,2,3
  • Caixia Guo3,4,5
6 affiliations
  1. 1Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101 ,
  2. 2Beijing Institute for Stem Cell and Regenerative Medicine , Beijing 100101 ,
  3. 3University of Chinese Academy of Sciences , Beijing 100049 ,
  4. 4China National Center for Bioinformation , Beijing 100101 ,
  5. 5Beijing Institute of Genomics, Chinese Academy of Sciences , Beijing 100101 ,
  6. 6Nanjing Maternal and Child Health Institute, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital , Nanjing 210004 ,
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Abstract

RAD52 and CHK1 are critical factors that play pleiotropic roles in the DNA damage response (DDR), including the resolution of transcription–replication conflicts (TRCs). However, how their functions are modulated remains incomplete. Here, we reveal that the cleavage and polyadenylation specificity factor subunit 6 (CPSF6) is an unexpected DDR factor that enhances RAD52 stability and CHK1 activation. Specifically, CPSF6 competitively interacts with RAD52, thereby preventing RAD52 from interacting with the E3 ubiquitin ligase UHRF1 and subsequent proteasomal degradation. In addition, CPSF6 enhances the ATR–CHK1 interaction to promote CHK1 activation, thereby facilitating the activation of downstream CHK1–PLK1–RAD51 pathway. The dual functions of CPSF6 in RAD52 stabilization and CHK1 activation contribute to its role in TRC resolution. CPSF6 depletion causes R-loop accumulation and transcription-associated DNA damage. Notably, these roles of CPSF6 in the DDR are independent of its canonical role in pre-mRNA 3′-end processing. Collectively, our findings establish that CPSF6 is a novel factor critical for maintaining genomic stability, with the resolution of TRCs as an important mechanism.

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Cite

BibTeXRIS
BibTeX
@article{wu2026cpsf6,
  title = {{CPSF6 maintains genomic stability by stabilizing RAD52 and promoting CHK1 activation}},
  author = {Honglin Wu and Hui Fu and Zhenzhen Fan and Junying Qin and Yifei Gong and Hui Zheng and Ruiyuan An and Xiuxiu Miao and Tie-Shan Tang and Caixia Guo},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag1011},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1011/8986611},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - CPSF6 maintains genomic stability by stabilizing RAD52 and promoting CHK1 activation
AU  - Honglin Wu
AU  - Hui Fu
AU  - Zhenzhen Fan
AU  - Junying Qin
AU  - Yifei Gong
AU  - Hui Zheng
AU  - Ruiyuan An
AU  - Xiuxiu Miao
AU  - Tie-Shan Tang
AU  - Caixia Guo
PY  - 2026
DA  - 2026/10/23
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag1011
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1011/8986611
AB  - RAD52 and CHK1 are critical factors that play pleiotropic roles in the DNA damage response (DDR), including the resolution of transcription–replication conflicts (TRCs). However, how their functions are modulated remains incomplete. Here, we reveal that the cleavage and polyadenylation specificity factor subunit 6 (CPSF6) is an unexpected DDR factor that enhances RAD52 stability and CHK1 activation. Specifically, CPSF6 competitively interacts with RAD52, thereby preventing RAD52 from interacting with the E3 ubiquitin ligase UHRF1 and subsequent proteasomal degradation. In addition, CPSF6 enhances the ATR–CHK1 interaction to promote CHK1 activation, thereby facilitating the activation of downstream CHK1–PLK1–RAD51 pathway. The dual functions of CPSF6 in RAD52 stabilization and CHK1 activation contribute to its role in TRC resolution. CPSF6 depletion causes R-loop accumulation and transcription-associated DNA damage. Notably, these roles of CPSF6 in the DDR are independent of its canonical role in pre-mRNA 3′-end processing. Collectively, our findings establish that CPSF6 is a novel factor critical for maintaining genomic stability, with the resolution of TRCs as an important mechanism.
SN  - 0305-1048
SN  - 1362-4962
ER  -