The PARP1-EXD2 axis orchestrates R-loop resolution to safeguard genome stability

  • Nat Chem Biol. 2025 Jun 27. doi: 10.1038/s41589-025-01952-x.
Zhaoshuang Li  #  1  2  3  4 ,  Yu Liu  #  2  3 ,  Yuanhui Liu  #  5 ,  Yiting Zhang  2  3 ,  Michael Shing Yan Huen  6 ,  Huasong Lu  2 ,  Zhigang Zhang  1 ,  Jianwei Zhou  7 ,  Dong Fang  8 ,  Ting Liu  9  10 ,  Jun Huang  11  12  13  14
Affiliations
  • 1. Department of Gynecology, The Second Affiliated Hospital, School of Medicine and Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 2. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 3. Cancer Center, Zhejiang University, Hangzhou, China.
  • 4. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China.
  • 5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6. School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 7. Department of Gynecology, The Second Affiliated Hospital, School of Medicine and Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 8. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Department of Gynecology, The Second Affiliated Hospital, School of Medicine and Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 10. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 11. Department of Gynecology, The Second Affiliated Hospital, School of Medicine and Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 12. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 13. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • 14. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China. [email protected].
  • # Contributed equally.
PMID: 40579572 DOI: 10.1038/s41589-025-01952-x
Abstract

R-loops, comprising an RNA-DNA hybrid and a displaced single-stranded DNA, are dynamic three-stranded nucleic acid structures that, when dysregulated, can disrupt transcription and replication, undermining genome integrity and contributing to human pathologies. Here we identify exonuclease 3'-5' domain-containing 2 (EXD2) as a pivotal R-loop resolvase. We demonstrate that EXD2, through direct interaction with poly(ADP-ribose) (PAR) Polymers synthesized by R-loop-bound and activated PAR polymerase 1 (PARP1), is recruited to R-loops, where it undergoes acetylation by the acetyltransferase CREB-binding protein at K416. This modification increases EXD2's binding affinity toward R-loop structures, allowing stable association with these structures despite the rapid turnover of PAR Polymers. Once retained, EXD2 preferentially degrades RNA strands within R-loops to promote their resolution. Loss of EXD2 results in the intracellular accumulation of R-loops, exacerbating transcription-replication conflicts and ultimately leading to genomic instability. These findings support a model in which R-loop-triggered PARP1 activation orchestrates EXD2-mediated resolution of R-loops, thereby preserving genome stability.

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