Mechanism of DNA degradation by CBASS Cap5 endonuclease immune effector

Olga Rechkoblit (), Daniela Sciaky, Mi Ni, Yangmei Li, Jithesh Kottur, Gang Fang and Aneel K. Aggarwal ()
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Olga Rechkoblit: Icahn School of Medicine at Mount Sinai
Daniela Sciaky: Icahn School of Medicine at Mount Sinai
Mi Ni: Icahn School of Medicine at Mount Sinai
Yangmei Li: Icahn School of Medicine at Mount Sinai
Jithesh Kottur: Icahn School of Medicine at Mount Sinai
Gang Fang: Icahn School of Medicine at Mount Sinai
Aneel K. Aggarwal: Icahn School of Medicine at Mount Sinai

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract Bacterial CBASS immune defense systems commonly kill virally infected cells by degrading genomic DNA in a form of cell suicide or abortive infection. We present a high-resolution structure of the CBASS effector Cap5, activated by a cyclic nucleotide, in the act of digesting DNA via tetrameric HNH endonuclease domains. Two HNH domains are in a catalytically active state for cleavage of the DNA strands, whereas the other two HNH domains are in a topologically distinct catalytically inactive state for simply DNA binding. The four HNH domains track one face of the DNA and mark an enzyme that acts as a stand-alone non-specific nuclease. We also show that chromosomally encoded CBASS Cap5 can be extrinsically activated by a cyclic nucleotide, as a step towards potential antibiotics.

Date: 2025
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DOI: 10.1038/s41467-025-60484-z

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