Peter H Yoon, Kenneth J Loi, Zeyuan Terry Zhang, Trevor A Docter, Santiago C Lopez, Conner J Langeberg, Muhammad Moez Ur-Rehman, Kamakshi Vohra, Zehan Zhou, Isabel Esain-Garcia, Marena I Trinidad, Honglue Shi, Ron Boger, Peter Y Wang, Benjamin A Adler, Stephen G Brohawn, Jennifer A Doudna
CRISPR-Cas provides RNA-mediated adaptive immunity, but how its first RNA-guided effector arose is unclear. In this study, we report the discovery of Viral Interference Programmable Repeat (VIPR) systems consisting of a Vipr protein ancestral to the earliest CRISPR-Cas effectors and VIPR RNAs (vrRNAs) comprising alternating GGY/NN motifs. Unlike canonical guide RNAs that pair with target nucleic acids through contiguous complementarity, vrRNAs recognize double-stranded DNA through a noncontiguous code in which the variable NN dinucleotides collectively specify a gapped target sequence. Natural vrRNA targets suggest that VIPR systems act against competing phages, and we demonstrate programmable phage defense by redirecting the complex for transcriptional repression. These results suggest that adaptive immunity originated from ancient warfare between viruses, revealing a previously unidentified logic for encoding information in sequence.