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Peer-reviewedCC BY-NC-NDNature communications

A phage DUF669 protein mediates post-cleavage DNA repair against host CRISPR immunity.

  • Heng Zhu1,2
  • Shengkun Dai1
  • Hewen Deng1
  • Shifeng Hou1
  • Yuelong Li3
  • Xin Tan1
  • Ning Jia3
  • Nan Li4
  • Yingfei Ma5,6
6 affiliations
  1. 1State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  2. 2University of Chinese Academy of Sciences, Beijing, China.
  3. 3Department of Biochemistry, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, China.
  4. 4State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  5. 5State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  6. 6University of Chinese Academy of Sciences, Beijing, China. [email protected].
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Abstract

Phages have evolved various anti-CRISPR (Acr) proteins or RNA-based anti-CRISPR (Racr) to evade host CRISPR immunity by direct interference. However, whether other counter-CRISPR mechanisms exist remains unexplored. Here, we report a phage-encoded two-protein system, termed Healer, which neutralizes CRISPR immunity via a post-cleavage DNA repair mechanism. This phage replication-associated system comprises two proteins: Gp63 (a DUF669 domain-containing protein), and Gp64 (an AAA domain-containing protein). Mechanistic investigations elucidate that Gp63 acts as a rapid-response effector of CRISPR-induced DNA breaks. After Gp63 binds ssDNA, it promotes Gp64-mediated homologous recombination, which repairs CRISPR-generated phage DNA breaks and supports phage viability. Notably, co-expression of the Healer system with Cas9/Cas12 in E. coli, P. aeruginosa, and A. baumannii demonstrated high phage genome-editing efficiency. Collectively, our findings reveal an important anti-CRISPR complementary strategy, providing a promising tool for genome engineering.

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Cite

BibTeXRIS
BibTeX
@article{zhu2026phage,
  title = {{A phage DUF669 protein mediates post-cleavage DNA repair against host CRISPR immunity.}},
  author = {Heng Zhu and Shengkun Dai and Hewen Deng and Shifeng Hou and Yuelong Li and Xin Tan and Ning Jia and Nan Li and Yingfei Ma},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77998-9},
  url = {https://europepmc.org/article/MED/42907433},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A phage DUF669 protein mediates post-cleavage DNA repair against host CRISPR immunity.
AU  - Heng Zhu
AU  - Shengkun Dai
AU  - Hewen Deng
AU  - Shifeng Hou
AU  - Yuelong Li
AU  - Xin Tan
AU  - Ning Jia
AU  - Nan Li
AU  - Yingfei Ma
PY  - 2026
DA  - 2026/09/21
JO  - Nature communications
DO  - 10.1038/s41467-026-77998-9
UR  - https://europepmc.org/article/MED/42907433
AB  - Phages have evolved various anti-CRISPR (Acr) proteins or RNA-based anti-CRISPR (Racr) to evade host CRISPR immunity by direct interference. However, whether other counter-CRISPR mechanisms exist remains unexplored. Here, we report a phage-encoded two-protein system, termed Healer, which neutralizes CRISPR immunity via a post-cleavage DNA repair mechanism. This phage replication-associated system comprises two proteins: Gp63 (a DUF669 domain-containing protein), and Gp64 (an AAA domain-containing protein). Mechanistic investigations elucidate that Gp63 acts as a rapid-response effector of CRISPR-induced DNA breaks. After Gp63 binds ssDNA, it promotes Gp64-mediated homologous recombination, which repairs CRISPR-generated phage DNA breaks and supports phage viability. Notably, co-expression of the Healer system with Cas9/Cas12 in E. coli, P. aeruginosa, and A. baumannii demonstrated high phage genome-editing efficiency. Collectively, our findings reveal an important anti-CRISPR complementary strategy, providing a promising tool for genome engineering.
SN  - 2041-1723
ER  -