Structural highlights
Publication Abstract from PubMedType IV-C CRISPR-Cas systems remain enigmatic compared to other class 1 systems. Here, we expand the type IV-C catalog, identifying two phylogenetically distinct clades primarily found in archaea (IV-C1) or bacteria (IV-C2), distinguishable by the Cas10IVc subunit architecture. We functionally and structurally characterize type IV-C1 systems from Thermococcus onnurineus (Ton) and Pyrococcus abyssi (Pab). Type IV-C complexes assemble with crRNAs derived from distinct CRISPR arrays and recognize a 5'-GGG-3' protospacer adjacent motif (PAM) to bind double-stranded DNA targets. Target recognition activates the HD domain of Cas10IVc, triggering metal-dependent collateral cleavage of single-stranded DNA and RNA. This behavior is explained by allosteric alignment of the HD active site, triggered by PAM-dependent R-loop formation, as revealed by cryo-EM. Together, our findings suggest that type IV-C systems provide immunity via non-specific cleavage of nucleic acids generated during mobile genetic element replication or transcription. Type IV-C CRISPR-Cas effector complexes recognize double-stranded DNA and switch on collateral cleavage of ssDNA and RNA.,Pittman CC, Xu C, Catchpole RJ, Garrett S, Fuchs R, Chu X, Makarova KS, Koonin EV, Zhao P, Wells L, Graveley BR, Ke A, Terns MP Cell Rep. 2026 Sep 5;45(9):117939. doi: 10.1016/j.celrep.2026.117939. PMID:42700392[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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