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Peer-reviewedCC BY 4.0Nucleic Acids Research

DNA defense systems become a fitness liability during plasmid conjugation

  • Jonathan N V Martinson1
  • Leo C T Song1,2
  • Benjamin E Rubin1
  1. 1Innovative Genomics Institute, University of California , Berkeley, CA 94720 ,
  2. 2Department of Comparative Biochemistry, University of California , Berkeley, CA 94720 ,
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Abstract

Horizontal gene transfer via conjugative plasmids is a major driver of bacterial evolution. While antibiotic exposure selects for the resistance genes carried by some plasmids, much uncertainty remains about how plasmids persist and spread in microbial communities in the absence of such external selection. Here, we show that conjugative plasmid transfer selectively reduces the fitness of non-permissive recipients through the process of lethal zygosis: a phenomenon in which repeated Type IV Secretion System (T4SS) engagement damages recipients that fail to establish the plasmid. We found that this contact-dependent antagonism effectively clears a niche for plasmid donors by turning recipients’ DNA defenses into a liability. Blocking establishment of the plasmid RK2 with CRISPR–Cas or restriction-modification caused strong fitness defects in Escherichia coli recipients by preventing expression of plasmid-encoded exclusion genes and leaving cells exposed to repeated T4SS engagement. We leveraged this insight to resolve an obstacle in bacterial editing by developing transposon vectors that co-deliver exclusion genes, increasing the efficiency of gene editing by orders of magnitude. Our results reveal the role of “coercive assimilation” in horizontal gene transfer, exposing a tradeoff where the advantage of bacterial immunity to foreign DNA is counterbalanced by increased susceptibility to lethal zygosis.

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Cite

BibTeXRIS
BibTeX
@article{martinson2026defense,
  title = {{DNA defense systems become a fitness liability during plasmid conjugation}},
  author = {Jonathan N V Martinson and Leo C T Song and Benjamin E Rubin},
  journal = {Nucleic Acids Research},
  year = {2026},
  month = oct,
  doi = {10.1093/nar/gkag1043},
  url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1043/9004251},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - DNA defense systems become a fitness liability during plasmid conjugation
AU  - Jonathan N V Martinson
AU  - Leo C T Song
AU  - Benjamin E Rubin
PY  - 2026
DA  - 2026/10/01
JO  - Nucleic Acids Research
DO  - 10.1093/nar/gkag1043
UR  - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1043/9004251
AB  - Horizontal gene transfer via conjugative plasmids is a major driver of bacterial evolution. While antibiotic exposure selects for the resistance genes carried by some plasmids, much uncertainty remains about how plasmids persist and spread in microbial communities in the absence of such external selection. Here, we show that conjugative plasmid transfer selectively reduces the fitness of non-permissive recipients through the process of lethal zygosis: a phenomenon in which repeated Type IV Secretion System (T4SS) engagement damages recipients that fail to establish the plasmid. We found that this contact-dependent antagonism effectively clears a niche for plasmid donors by turning recipients’ DNA defenses into a liability. Blocking establishment of the plasmid RK2 with CRISPR–Cas or restriction-modification caused strong fitness defects in Escherichia coli recipients by preventing expression of plasmid-encoded exclusion genes and leaving cells exposed to repeated T4SS engagement. We leveraged this insight to resolve an obstacle in bacterial editing by developing transposon vectors that co-deliver exclusion genes, increasing the efficiency of gene editing by orders of magnitude. Our results reveal the role of “coercive assimilation” in horizontal gene transfer, exposing a tradeoff where the advantage of bacterial immunity to foreign DNA is counterbalanced by increased susceptibility to lethal zygosis.
SN  - 0305-1048
SN  - 1362-4962
ER  -