A Noncontiguous Code for RNA-Guided DNA Recognition Preceded CRISPR

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.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-04-27
DOI
https://doi.org/10.64898/2026.04.26.720920
Citations
1
Primary Topic
CRISPR and Genetic Engineering
Type
article
Field-Weighted Citation Impact
11.57

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A Noncontiguous Code for RNA-Guided DNA Recognition Preceded CRISPR

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A Noncontiguous Code for RNA-Guided DNA Recognition Preceded CRISPR

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article en
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Abstract

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.

bioRxiv (Cold Spring Harbor Laboratory)
QB3 (US), Howard Hughes Medical Institute (US), Innovative Genomics Institute (US), University of California, Berkeley (US)
National Science Foundation, Howard Hughes Medical Institute, Emerson Collective, National Institutes of Health, Common Fund
Openalex Percentile: Top 1%
CRISPR and Genetic Engineering
11.57
DOIOpen Access PDFOpenAlex
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