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Phage-encoded homing endonucleases attenuate bacterial immunity

Mahata, T.; Kanarek, K.; Ragavan, R. M.; Haldar, A.; Shur, G.; Yehia, R.; Burstein, D.; Haitin, Y.; Qimron, U.; Salomon, D.

2025-09-07 microbiology
10.1101/2025.09.07.674715 bioRxiv
Show abstract

The arms race between bacteria and bacteriophages (phages) gave rise to multiple layers of antagonistic mechanisms, many of which remain unexplored. Here, we investigated the anti-phage defense system GAPS4 and showed that it is a non-selective DNase triggered by sensing DNA breaks. We further demonstrated that this activation mechanism renders GAPS4 a double-edged sword, sensitizing bacteria to various forms of antibacterial antagonism. Using comparative genomics, we found that phage-encoded homing endonucleases, long considered selfish mobile genetic elements, enhance phage fitness by attenuating GAPS4-mediated immunity. Our findings shed light on the evolutionary advantage provided by these ubiquitous mobile elements to their host phages, and on the intricate evolutionary cross-talk between bacteria and their predators.

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