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Alternative functions of CRISPR–Cas systems in the evolutionary arms race

Abstract

CRISPR–Cas systems of bacteria and archaea comprise chromosomal loci with typical repetitive clusters and associated genes encoding a range of Cas proteins. Adaptation of CRISPR arrays occurs when virus-derived and plasmid-derived sequences are integrated as new CRISPR spacers. Cas proteins use CRISPR-derived RNA guides to specifically recognize and cleave nucleic acids of invading mobile genetic elements. Apart from this role as an adaptive immune system, some CRISPR-associated nucleases are hijacked by mobile genetic elements: viruses use them to attack their prokaryotic hosts, and transposons have adopted CRISPR systems for guided transposition. In addition, some CRISPR–Cas systems control the expression of genes involved in bacterial physiology and virulence. Moreover, pathogenic bacteria may use their Cas nuclease activity indirectly to evade the human immune system or directly to invade the nucleus and damage the chromosomal DNA of infected human cells. Thus, the evolutionary arms race has led to the expansion of exciting variations in CRISPR mechanisms and functionalities. In this Review, we explore the latest insights into the diverse functions of CRISPR–Cas systems beyond adaptive immunity and discuss the implications for the development of CRISPR-based applications.

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Fig. 1: Collateral damage associated with CRISPR–Cas systems.
Fig. 2: CRISPR–Cas in the evolutionary arms race between phages and bacteria.
Fig. 3: Hijacking of CRISPR–Cas by mobile genetic elements.
Fig. 4: Function of CRISPR–Cas in the regulation of bacterial virulence.
Fig. 5: Direct role of CRISPR–Cas in bacterial virulence.

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Acknowledgements

The authors acknowledge financial support from the Dutch Research Council (NWO) (NWO TOP-grant 714.015.001) and the European Research Council (ERC-AdG-834279) to J.v.d.O. R.H.J.S was supported by the NWO (VIDI grant VI.Vidi.203.074). C.S. is a graduate student at the Erasmus Postgraduate School of Molecular Medicine and is partially supported by the I&I Fund (Erasmus Vrienden Fonds) and LSH-TKI foundation grant LSHM18006. R.L. is supported by the Department of Medical Microbiology and Infectious Diseases and the Department of Bioinformatics, Erasmus University Medical Center.

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P.M., R.H.J.S. and J.v.d.O. researched data for the article. All authors contributed substantially to the discussion of the content. P.M., R.H.J.S. and J.v.d.O. wrote the article. All authors reviewed/edited the manuscript before submission.

Corresponding authors

Correspondence to Raymond H. J. Staals or John van der Oost.

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Competing interests

J.v.d.O. is scientific advisor of NTrans Technologies, and J.v.d.O. and R.H.J.S. are scientific advisors of Scope Biosciences. P.M., P.v.B., R.L., R.H.J.S. and J.v.d.O. are included as inventors on CRISPR–Cas-related patents. C.S. declares no competing interests.

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Nature Reviews Microbiology thanks Luciano Marraffini and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Horizontal gene transfer

Exchange of genetic material between organisms that may be phylogenetically unrelated.

Transposons

Segments of DNA that can move within and between genomes by integrating into target sites using one or more transposon-encoded enzymes (transposase, recombinase or integrase).

Mobile genetic elements

(MGEs). Clusters of selfish genes, either naked or packaged in capsid-like structures, that need to invade cellular organisms for their replication and proliferation.

Evolutionary arms race

The continuous arms race of developing infection and anti-infection strategies resulting in a rapid co-evolution of the parasite’s offence systems and the host’s defence systems.

CRISPR array

Genomic locus located adjacent to the CRISPR-associated genes (cas genes), consisting of multiple variable spacer sequences separated by tandem invariable repeats.

Spacers

Unique segments of DNA that are frequently derived from viral genomes and plasmids, and that are inserted between repeats in a CRISPR array.

CRISPR RNA

Short RNA molecules, produced by primary processing of the long precursor transcript of a CRISPR array, consisting of a spacer flanked on one or both sides by repeat-derived handles. CRISPR RNAs guide the Cas protein(s) to target cognate foreign DNA or RNA.

Protospacer adjacent motif

(PAM). A short signature sequence flanking the protospacer that enables self–non-self discrimination. In most CRISPR–Cas systems, the PAM sequence is essential for both adaptation and target recognition.

Collateral cleavage

Nuclease activity exhibited by some Cas proteins leading to indiscriminate degradation of any nearby non-target single-stranded DNA or RNA, respectively, upon target recognition.

HD domain

A nuclease domain with a conserved catalytic site that includes a metal-binding histidine–aspartate (HD) pair. The HD domain of Cas3 and Cas10 in type I and type III CRISPR–Cas systems, respectively, is responsible for endonucleolytic degradation of DNA targets.

Palm domain

A domain typically found in nucleotide cyclases and polymerases (as part of their fingers, palm and thumb-like architecture). The palm domain in the type III Cas10 proteins is characterized by a conserved GGDD motif, which catalyses the cyclase reaction to form cyclic oligoadenylate messenger molecules from ATP molecules.

CRISPR-associated Rossman fold (CARF) domain

A domain often found fused to an effector domain with (ribo)nuclease activity or other catalytic activities. The CARF domain acts as a sensory domain that binds ligands (for example, cyclic oligoadenylate messenger molecules produced by Cas10 in type III systems) that allosterically activate the fused effector domain.

Burst size

The number of newly synthesized phage particles released from a bacterium infected by a single phage.

Helix–turn–helix (HTH) domain

A widespread domain found in many proteins that bind DNA. The domain is characterized by two α-helices that bind the major groove of double-stranded DNA.

trans-activating crRNA

(tracrRNA). RNA encoded by all known type II and some type V CRISPR–Cas systems that includes an antirepeat part that base-pairs with the repeat portion of CRISPR RNA (crRNA) to form a functional guide RNA. tracrRNA is essential for crRNA maturation and target interference in the respective CRISPR–Cas systems.

SOS response

A coordinated cellular response to genotoxic stress comprising an error-prone DNA repair system that allows restarting of stalled replication forks past lesions or errors.

Adeno-associated virus delivery

Transduction of genes to cells and organisms using adeno-associated viruses, which is generally considered safer than use of adenoviral and retroviral vectors. It can be used to transduce genes into both proliferating and non-proliferating cells, and can impart long-term expression in non-dividing cells.

Base editing

Genome editing technology that consists of a catalytically inactive CRISPR–Cas nuclease fused to a single-stranded DNA deaminase and, in some cases, to proteins that manipulate DNA repair machinery; cytosine base editors catalyse the conversion of C•G base pairs to T•A base pairs; and adenine base editors catalyse the conversion of A•T base pairs to G•C base pairs .

Prime editing

Genome editing technology based on the fusion proteins formed between a Cas9 nickase (inactivated HNH nuclease domain) and an engineered reverse transcriptase domain, including a synthetic single guide (prime editing guide RNA) consisting of CRISPR RNA, trans-activating CRISPR RNA and a prime editing extension.

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Mohanraju, P., Saha, C., van Baarlen, P. et al. Alternative functions of CRISPR–Cas systems in the evolutionary arms race. Nat Rev Microbiol 20, 351–364 (2022). https://doi.org/10.1038/s41579-021-00663-z

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