Yoon, P. H.; Loi, K. J.; Zhang, Z.; Docter, T. A.; Lopez, S. C.; Langeberg, C. J.; ur-Rehman, M. M.; Vohra, K.; Zhou, Z.; Shi, H.; Boger, R.; Wang, P. Y.; Adler, B. A.; Brohawn, S. G.; Doudna, J. A.

CRISPR-Cas systems use RNA-guided proteins for adaptive immunity through a mechanism whose origin is unknown. Here we report the discovery of Viral Interference Programmable Repeat (VIPR) systems consisting of a Vipr protein more ancient than CRISPR-Cas and vrRNAs comprising alternating GGY/NN motifs. Unlike canonical guide RNAs that base pair with nucleic acid targets using an uninterrupted sequence, vrRNAs recognize double-stranded DNA through a noncontiguous code in which the variable NNs of each repeat collectively specify a target that itself contains a gapped recognition sequence. Analysis of natural vrRNA targets suggests VIPR acts against competing phages. We demonstrate programmable phage defense by redirecting the complex for transcriptional repression. These results suggest that the roots of adaptive immunity lie in ancient warfare between viruses, and reveal a new logic for programmable genetic control.