A temperature-driven DNA discrimination strategy to distinguish <i>E. coli</i> DNA and phage 5hmC-modified DNA
The arms race between phages and bacteria is dynamic and ongoing, with both continuously acquiring new strategies to outcompete each other during co-evolution. Here, we report bacteriophage T4 exonuclease DexA and an uncharacterized Escherichia coli exonuclease as a rare pair of attack and defense duo arising from the same mechanism. DexA, highly conserved among phages, has two well-characterized biological roles: host DNA scavenging and intron homing. Unmodified DNA is the substrate during host DNA scavenging, whereas cleavage of 5hmC (5-hydroxymethylcytosine)-modified phage DNA is required for intron homing. We reveal a temperature-driven quaternary fold switch between DexA dimer and tetramer that facilitates cleavage of distinct DNA forms, namely 5hmC-modified phage DNA and unmodified host DNA. As a countermeasure, bacteria produce DexA variants for defense against phage that only targets 5hmC-modified DNA. Thus, both phages and bacteria compete using HmC-Recognizing EXonuclease strategies (designated as HREX).
Authors
- Hao‐Long Zhou (ORCID: https://orcid.org/0000-0002-5007-6535)
- Shuai Yuan (ORCID: https://orcid.org/0000-0003-4037-3429)
- Chengpeng Fan (ORCID: https://orcid.org/0000-0001-9428-9463)
- Yingqi Xu (ORCID: https://orcid.org/0000-0001-6861-7355)
- S. Matthews (ORCID: https://orcid.org/0000-0003-3556-962X)
- Biyun Ma
- Huaiyu Yang (ORCID: https://orcid.org/0000-0002-3905-436X)
- Yahui Liu
- Bing Liu (ORCID: https://orcid.org/0000-0003-1670-6115)
- Yawen Wang (ORCID: https://orcid.org/0000-0002-1306-8931)
- Yan Li (ORCID: https://orcid.org/0000-0002-1612-5719)
- Huan Chen (ORCID: https://orcid.org/0000-0002-5089-2719)
- Kaining Zhang (ORCID: https://orcid.org/0000-0001-5275-6633)
- Yue Kang (ORCID: https://orcid.org/0000-0003-3244-8347)
Institutions
- Loughborough University (GB)
- Chinese Academy of Sciences (CN)
- Wuhan University (CN)
- Wuhan Institute of Virology (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Imperial College London (GB)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1093/nar/gkaf501
- Citations
- 1
- Primary Topic
- Bacteriophages and microbial interactions
- Type
- article
- Field-Weighted Citation Impact
- 1.72
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities