TraitMech

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ENDPaCF1 system

traitmech:000503 · CLASS · PROPOSED

A phage defense system in which an organism possesses an ENDPaCF1 Type IIS restriction endonuclease-like locus with an inactive Endonuclease III sensing domain that can recognize diverse DNA hypermodifications and protect bacteria from hypermodified phages.

Trait evidence (7)

  • DOI:10.1101/2025.03.31.646159
    The causal defense system is a Type IIS restriction endonuclease-like protein (ENDPaCF1), common in Pseudomonads, however it lacks an associated methyltransferase typical Type IIS R-M systems.

    Yee et al. identify ENDPaCF1 as the causal Pseudomonas antiphage system and distinguish it from canonical Type IIS restriction-modification systems.

  • DOI:10.1101/2025.03.31.646159
    ENDPaCF1 protects bacteria against phages with hypermodified DNA and is surprisingly agnostic to the specific structure of the modification, which is unlike typical type IV restriction endonucleases.

    Yee et al. connect ENDPaCF1 to protection against phages with multiple hypermodified-DNA chemistries.

  • DOI:10.1101/2025.03.31.646159
    Here, we employed the CRISPR-based Cascade-Cas3 system to delete defense islands in a Pseudomonas aeruginosa clinical isolate to identify mechanisms of lytic phage antagonism. Deletion of one island in a cystic fibrosis-derived clinical isolate sensitized the strain to phages from the Pbunavirus family, which are commonly used as therapeutics.

    Yee et al. identified the ENDPaCF1 island as an endogenous Pseudomonas aeruginosa phage-defense determinant.

  • DOI:10.1101/2025.03.31.646159
    In ENDPaCF1, the endonuclease domain is fused to a catalytically inactive Endonuclease III (iEndoIII), a domain that recognizes non-canonical bases to repair DNA in prokaryotes and eukaryotes.

    Yee et al. describe the ENDPaCF1 endonuclease plus inactive Endonuclease III domain architecture.

  • DOI:10.1101/2025.03.31.646159
    We therefore propose that nucleases containing an iEndoIII domain (END nucleases) can sense diverse DNA hypermodifications.

    Yee et al. propose the END nuclease family around the iEndoIII domain's ability to sense diverse DNA modifications.

  • DOI:10.1101/2025.03.31.646159
    We further show that some hypermodified phages, including Pbunavirus family members and Wrowclawvirus family (Pa5oct-like) of jumbo phages, encode END nuclease inhibitors that directly bind to the nuclease, likely via the iEndoIII domain.

    Yee et al. support direct phage inhibitor binding to END nucleases while leaving ENDPaCF1 inhibitor breadth unresolved.

  • https://raw.githubusercontent.com/mdmparis/defense-finder-models/afb0e5a8b466be53586b13266f5d38d98c3ac268/List_system_article.md
    | ENDPaCF1 | 10\.1101/2025\.03\.31\.646159 | END nucleases: Antiphage defense systems targeting multiple hypermodified phage genomes |

    The pinned DefenseFinder article registry maps the ENDPaCF1 source key to the Yee et al. bioRxiv preprint.

ENDPaCF1 targets hypermodified phage DNA

Conservative system-level sketch linking an ENDPaCF1 locus to iEndoIII-linked sensing of hypermodified phage DNA, modification-dependent endonuclease targeting, phage restriction, and ENDPaCF1 system possession.

NONMECHANISTIC · The graph captures ENDPaCF1 as a named single-protein phage-defense system with Type IIS restriction endonuclease-like and iEndoIII domains while leaving Pseudomonas natural host breadth, complete DNA-modification breadth, direct domain coupling, phage-inhibitor specificity, and DefenseFinder HMM/rules detection criteria unresolved.

ENDPaCF1 targets hypermodified phage DNA Interactive directed graph showing evidence-backed causal relationships for ENDPaCF1 system.

Edge evidence

  • ENDPaCF1 locus enables hypermodified phage DNA sensing RO:0002327

    An ENDPaCF1 locus enables sensing of diverse hypermodified phage genomes.

    • DOI:10.1101/2025.03.31.646159 The causal defense system is a Type IIS restriction endonuclease-like protein (ENDPaCF1), common in Pseudomonads, however it lacks an associated methyltransferase typical Type IIS R-M systems. Yee et al. identify ENDPaCF1 as the causal Pseudomonas antiphage system and distinguish it from canonical Type IIS restriction-modification systems.
    • DOI:10.1101/2025.03.31.646159 In ENDPaCF1, the endonuclease domain is fused to a catalytically inactive Endonuclease III (iEndoIII), a domain that recognizes non-canonical bases to repair DNA in prokaryotes and eukaryotes. Yee et al. describe the ENDPaCF1 endonuclease plus inactive Endonuclease III domain architecture.
    • DOI:10.1101/2025.03.31.646159 We therefore propose that nucleases containing an iEndoIII domain (END nucleases) can sense diverse DNA hypermodifications. Yee et al. propose the END nuclease family around the iEndoIII domain's ability to sense diverse DNA modifications.
    • https://raw.githubusercontent.com/mdmparis/defense-finder-models/afb0e5a8b466be53586b13266f5d38d98c3ac268/List_system_article.md | ENDPaCF1 | 10\.1101/2025\.03\.31\.646159 | END nucleases: Antiphage defense systems targeting multiple hypermodified phage genomes | The pinned DefenseFinder article registry maps the ENDPaCF1 source key to the Yee et al. bioRxiv preprint.
  • hypermodified phage infection contributes to hypermodified phage DNA sensing RO:0002326

    Hypermodified phage genomes provide the substrate recognized by ENDPaCF1-family END nucleases.

    • DOI:10.1101/2025.03.31.646159 ENDPaCF1 protects bacteria against phages with hypermodified DNA and is surprisingly agnostic to the specific structure of the modification, which is unlike typical type IV restriction endonucleases. Yee et al. connect ENDPaCF1 to protection against phages with multiple hypermodified-DNA chemistries.
  • modification-dependent phage DNA cleavage mitigates hypermodified phage infection METPO:2007407

    Modification-dependent phage DNA cleavage protects bacteria against phages with hypermodified DNA.

    • DOI:10.1101/2025.03.31.646159 ENDPaCF1 protects bacteria against phages with hypermodified DNA and is surprisingly agnostic to the specific structure of the modification, which is unlike typical type IV restriction endonucleases. Yee et al. connect ENDPaCF1 to protection against phages with multiple hypermodified-DNA chemistries.
  • modification-dependent phage DNA cleavage confers ENDPaCF1 system METPO:2007700

    ENDPaCF1-family targeting of hypermodified phage DNA realizes the ENDPaCF1 system trait.

    • DOI:10.1101/2025.03.31.646159 Our findings reveal modularity of the sensing and cleavage domains, as expected of a modification-dependent endonucleases. Yee et al. frame END nuclease activity as modification-dependent coupling between sensing and cleavage domains.
  • ENDPaCF1 system is a phage defense system rdfs:subClassOf

    ENDPaCF1 system possession is a phage-defense-system trait.

Provenance

Identifier source
TraitMech local identifier
Definition source
DOI:10.1101/2025.03.31.646159

Parent traits (1)

Synonyms (1)

  • ENDPaCF1 EXACT_SYNONYM · https://raw.githubusercontent.com/mdmparis/defense-finder-models/afb0e5a8b466be53586b13266f5d38d98c3ac268/List_system_article.md

kg-microbe context

No kg-microbe node embedding matched this record in the 2026-04-25 deepwalk.

Canonical examples (1)

Organisms cited as exemplars of this trait. Taxon ids are NCBITaxon and link out to the NCBI record.

  • Pseudomonas aeruginosa NCBITaxon:287 DOI:10.1101/2025.03.31.646159 Yee et al. identified ENDPaCF1 in the cystic-fibrosis-derived clinical isolate CF040 and showed that deleting the ENDPaCF1-bearing defense island sensitized the native Pseudomonas aeruginosa strain to Pbunavirus phages.

Discussions and Knowledge Gaps (1)

Open questions attached to this trait. Seeded by just knowledge-gap-scan and curated; see the corpus-wide index.

Resolve ENDPaCF1 Pseudomonas host breadth, complete phage-DNA hypermodification breadth, direct iEndoIII sensing-to-cleavage coupling, phage inhibitor specificity, and DefenseFinder HMM/rules coverage before minting narrower END nuclease mechanism or component traits.

KNOWLEDGE GAP OPEN endpacf1-host-modification-and-model-gap · raised by codex · 2026-09-30

Attached to causal_graphs#endpacf1_targets_hypermodified_phage_dna

Yee et al. support ENDPaCF1 as a Type IIS restriction endonuclease-like Pseudomonas phage-defense system that can recognize diverse hypermodified phage genomes, and the pinned DefenseFinder article registry maps the ENDPaCF1 source key to the Yee et al. preprint. The pinned HMM inventory and rules table have no exact ENDPaCF1 rows. This first-pass record therefore does not resolve a complete profile model, the direct domain coupling between iEndoIII sensing and cleavage, or the full natural host, phage, and inhibitor breadth.

Evidence

Curation history

  1. · MINTED_TRAITMECH_ID · codex

    Minted ENDPaCF1 system as a bioRxiv- and DefenseFinder-backed GENOMICS TraitRecord under phage defense system after an ignored-and-hidden duplicate review found no exact live TraitMech, METPO, history, research, generated, or prior proposal record; kept the graph at Type IIS restriction-endonuclease-like system level because the pinned DefenseFinder article row is not backed by pinned HMM or rules rows; the replacement placeholder is reserved in proposals/metpo_traitmech_v380.

  2. · REVIEW_CANONICAL_EXAMPLE_EVIDENCE_GAP · codex

    Reviewed ENDPaCF1 system canonical_examples and left them empty because public preprint and DefenseFinder evidence supports the named phage-defense system but not a direct named native microbial isolate exemplar with experimentally verified endogenous ENDPaCF1 activity. No paid research was used.

  3. · ADDRESS_ENDPACF1_REVIEW_FINDINGS · codex

    Addressed Copilot review issues #1501, #1502, and #1503: added Pseudomonas aeruginosa (NCBITaxon:287) as a DOI-backed native ENDPaCF1 canonical example, removed the unsupported direct hypermodified-phage-DNA-sensing to modification-dependent-phage-DNA-cleavage causal edge, and included the discussions block in the repository CREATE history sections.