Cyclic oligoadenylate signaling and regulation by ring nucleases during type III CRISPR defense

Januka S Athukoralage*, Malcolm F White

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


In prokaryotes, CRISPR-Cas immune systems recognise and cleave foreign nucleic acids to defend against Mobile Genetic Elements (MGEs). Type III CRISPR-Cas complexes also synthesise cyclic oligoadenylate (cOA) second messengers, which activate CRISPR ancillary proteins involved in antiviral defence. In particular, cOA-stimulated nucleases degrade RNA and DNA non-specifically, which slows MGE replication but also impedes cell growth, necessitating mechanisms to eliminate cOA in order to mitigate collateral damage. Extant cOA is degraded by a new class of enzyme termed a 'ring nuclease', which cleaves cOA specifically and switches off CRISPR ancillary enzymes. Several ring nuclease families have been characterised to date, including a family used by MGEs to circumvent CRISPR immunity, and encompass diverse protein folds and distinct cOA cleavage mechanisms. In this review we outline cOA signalling, discuss how different ring nucleases regulate the cOA signalling pathway, and reflect on parallels between cyclic nucleotide-based immune systems to reveal new areas for exploration.
Original languageEnglish
Pages (from-to)855-867
Number of pages13
Issue number8
Early online date13 May 2021
Publication statusPublished - 1 Aug 2021


  • CARF
  • CRISPR-Cas
  • Csm6 ribonuclease
  • Cyclic nucleotides
  • Ring nuclease
  • Nucleic-acid detection
  • RNA cleavage
  • DNA cleavage
  • CAS
  • Complex
  • Mechanism
  • CGAS
  • CSX3
  • Specificity
  • Recognition


Dive into the research topics of 'Cyclic oligoadenylate signaling and regulation by ring nucleases during type III CRISPR defense'. Together they form a unique fingerprint.

Cite this