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bioRxiv · 10.1101/2025.09.07.674715

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.
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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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Mahata, T., Kanarek, K., Ragavan, R. M., Haldar, A., Shur, G., Yehia, R., Burstein, D., Haitin, Y., Qimron, U., Salomon, D.. 2025-09-07. Phage-encoded homing endonucleases attenuate bacterial immunity. https://doi.org/10.1101/2025.09.07.674715

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