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Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems


Cyclic-oligonucleotide-based anti-phage signalling systems (CBASS) are a family of defence systems against bacteriophages (hereafter phages) that share ancestry with the cGAS–STING innate immune pathway in animals. CBASS systems are composed of an oligonucleotide cyclase, which generates signalling cyclic oligonucleotides in response to phage infection, and an effector that is activated by the cyclic oligonucleotides and promotes cell death. Cell death occurs before phage replication is completed, therefore preventing the spread of phages to nearby cells. Here, we analysed 38,000 bacterial and archaeal genomes and identified more than 5,000 CBASS systems, which have diverse architectures with multiple signalling molecules, effectors and ancillary genes. We propose a classification system for CBASS that groups systems according to their operon organization, signalling molecules and effector function. Four major CBASS types were identified, sharing at least six effector subtypes that promote cell death by membrane impairment, DNA degradation or other means. We observed evidence of extensive gain and loss of CBASS systems, as well as shuffling of effector genes between systems. We expect that our classification and nomenclature scheme will guide future research in the developing CBASS field.

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Fig. 1: General description of CBASS systems.
Fig. 2: Phylogenetic distribution of CBASS types and effectors.
Fig. 3: Rapid gain and loss of and gene shuffling in CBASS systems.

Data availability

All genomic data that support the findings of this study are available at IMG ( Accession codes for all data are provided in Supplementary Tables 17. PDB and Pfam databases are available at the HHsuite database page (


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We thank the members of the Sorek laboratory for comments on earlier versions of this manuscript. A.M. was supported by a fellowship from the Ariane de Rothschild Women Doctoral Program and, in part, by the Israeli Council for Higher Education via the Weizmann Data Science Research Center. R.S. was supported in part by the Israel Science Foundation (personal grant no. 1360/16), the European Research Council (grant no. ERC-CoG 681203), the German Research Council (DFG) priority program SPP 2002 (grant no. SO 1611/1-1), the Israeli Council for Higher Education through the Weizmann Data Science Research Center, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Minerva Foundation with funding from the Federal German Ministry for Education and Research and the Knell Family Center for Microbiology.

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Authors and Affiliations



A.M. collected and analysed the data and wrote the paper. S.M. and G.A. were involved in the classification of CBASS systems. R.S. supervised the study and wrote the paper.

Corresponding author

Correspondence to Rotem Sorek.

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Competing interests

R.S. is a scientific cofounder and consultant of BiomX, Pantheon Bioscience and Ecophage.

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Extended data

Extended Data Fig. 1 Phylogenetic analysis of oligonucleotide cyclases (CD-NTase) and their CBASS types.

The phylogenetic tree of all cyclases, as depicted and colored in refs (5 and 8) is presented in the center. Each clade is then expanded and presented in the periphery as a circular tree to increase resolution. Outer ring depicts the effector type; middle ring depicts the system type. Numbers next to each clade represent the bootstrap value for that node in the central tree.

Supplementary information

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Supplementary Tables

Supplementary Tables 1–7.

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Millman, A., Melamed, S., Amitai, G. et al. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Nat Microbiol 5, 1608–1615 (2020).

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