ABSTRACT The principal function of CRISPR–Cas systems in archaea and bacteria is defence against mobile genetic elements (MGEs), including viruses, plasmids and transposons. However, the

relationships between CRISPR–Cas and MGEs are far more complex. Several classes of MGE contributed to the origin and evolution of CRISPR–Cas, and, conversely, CRISPR–Cas systems and their

components were recruited by various MGEs for functions that remain largely uncharacterized. In this Analysis article, we investigate and substantially expand the range of CRISPR–Cas

components carried by MGEs. Three groups of Tn7-like transposable elements encode ‘minimal’ type I CRISPR–Cas derivatives capable of target recognition but not cleavage, and another group

carry CRISPR mini-arrays, some of which recognize other viruses and are implicated in inter-virus conflicts, and solitary repeat units, which could inhibit host CRISPR–Cas systems. Access

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ALTERNATIVE FUNCTIONS OF CRISPR–CAS SYSTEMS IN THE EVOLUTIONARY ARMS RACE Article 06 January 2022 TRANSPOSON-ENCODED NUCLEASES USE GUIDE RNAS TO PROMOTE THEIR SELFISH SPREAD Article 27

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phage search tool. _Nucleic Acids Res._ 44, W16–W21 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS G.F., S.A.S., K.S.M. and E.V.K. are

supported by funds from the Intramural Research Program of the National Institutes of Health of the USA. S.A.S. was additionally supported by the Russian Foundation for Basic Research

(research project 18-34-00012) and a systems biology fellowship from Philip Morris Sales and Marketing. J.E.P. was supported by the US Department of Agriculture National Institute of Food

and Agriculture Hatch Project NYC-189438. D.R.C., W.X.Y. and D.A.S. are supported by Arbor Biotechnologies. REVIEWER INFORMATION _Nature Reviews Microbiology_ thanks U. Gophna, and other

anonymous reviewer(s), for their contribution to the peer review of this work. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * National Center for Biotechnology Information, National Library

of Medicine, National Institutes of Health, Bethesda, MD, USA Guilhem Faure, Sergey A. Shmakov, Kira S. Makarova & Eugene V. Koonin * Broad Institute of MIT and Harvard, Cambridge, MA,

USA Guilhem Faure * Skolkovo Institute of Science and Technology, Skolkovo, Russia Sergey A. Shmakov * Arbor Biotechnologies, Cambridge, MA, USA Winston X. Yan, David R. Cheng & David A.

Scott * Department of Microbiology, Cornell University, Ithaca, NY, USA Joseph E. Peters Authors * Guilhem Faure View author publications You can also search for this author inPubMed Google

Scholar * Sergey A. Shmakov View author publications You can also search for this author inPubMed Google Scholar * Winston X. Yan View author publications You can also search for this

author inPubMed Google Scholar * David R. Cheng View author publications You can also search for this author inPubMed Google Scholar * David A. Scott View author publications You can also

search for this author inPubMed Google Scholar * Joseph E. Peters View author publications You can also search for this author inPubMed Google Scholar * Kira S. Makarova View author

publications You can also search for this author inPubMed Google Scholar * Eugene V. Koonin View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

G.F., S.A.S., W.X.Y., D.R.C., D.A.S., J.E.P., K.S.M. and E.V.K. researched the data for the article. G.F., W.X.Y., D.R.C., D.A.S., J.E.P., K.S.M. and E.V.K. substantially contributed to the

discussion of the content. E.V.K. wrote the article. G.F., W.X.Y., D.R.C., D.A.S., J.E.P., K.S.M. and E.V.K. reviewed and edited the manuscript before submission. CORRESPONDING AUTHOR

Correspondence to Eugene V. Koonin. ETHICS DECLARATIONS COMPETING INTERESTS D.R.C., W.X.Y. and D.A.S. are shareholders of Arbor Biotechnologies. All other authors declare no competing

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INFORMATION SUPPLEMENTARY INFORMATION SUPPLEMENTARY DATASET 1 SUPPLEMENTARY DATASET 2 SUPPLEMENTARY DATASET 3 SUPPLEMENTARY DATASET 4 SUPPLEMENTARY DATASET 5 GLOSSARY * CRISPR spacers Unique

sequences of 20–60 nucleotides inserted between the repeats in the CRISPR array and employed, as part of the CRISPR RNA, for targeting DNA molecules containing a homologous protospacer. *

CRISPR array A series of direct repeats in bacterial and archaeal genomes interspersed with spacers that are acquired primarily from mobile genetic element DNA. * crRNAs Short RNAs, produced

by processing of the primary transcript of a CRISPR array, that consists of a spacer and portions of the flanking repeats and functions as a guide to target DNA or RNA molecules containing

cognate protospacers. * Mini-arrays Minimal forms of a CRISPR array that consists of a proximal repeat, a spacer and a distal repeat, or, more commonly, a partial repeat; so far identified

in virus and provirus genomes. * Solitary repeat units (SRUs). Short sequences, so far identified in virus and provirus genomes, that are (nearly) identical to a repeat from a CRISPR array.

* CRISPR adaptation module A group of _cas_ genes dedicated to the selection and insertion of new spacers into CRISPR arrays. * TnpB A nuclease containing a RuvC-like domain that is encoded

by numerous transposons (insertion sequences) although not required for transposition. * IS605-like transposons A family of bacterial and archaeal insertion sequence elements that encode a

distinct transposase (TnpA) and often a second nuclease (TnpB) that is also found in numerous non-autonomous IS605-like transposons lacking TnpA. * Tn7-like transposons A derivative of Tn7

family transposons lacking some accessory genes involved in transposition and in some cases carrying derived CRISPR–Cas systems lacking the interference capacity. * CRISPR effector module A

suite of Cas proteins (Class 1 CRISPR–Cas systems) or a single large protein (Class 2 CRISPR–Cas systems) that are responsible for maturation of the CRISPR RNA and interference. * R-loops

Three-stranded structures that consist of a DNA–RNA hybrid and the displaced single-stranded DNA, formed during transcription and other processes including target recognition by CRISPR–Cas

effector complexes (proteins). * Protospacer A piece of DNA, typically from a mobile genetic element genome, that is inserted into a CRISPR array by the CRISPR adaptation complex, to become

a spacer. * CysH enzymes Enzymes of the adenosine 5′-phosphosulfate reductase family that reduce activated sulfate to sulfite; associated with many type IV CRISPR–Cas systems. * Exaptation

Co-option (recruitment) of a biological entity, such as a protein or DNA sequence, for a role that is distinct from its original function. * Anti-CRISPR proteins Diverse proteins encoded by

many bacterial and archaeal viruses that inhibit the host CRISPR–Cas systems, typically by binding and inactivating the effector complex (protein). * _Trans_activating RNAs (tracrRNAs). RNA

molecules encoded by all known type II CRISPR–Cas systems and some type V systems that consist of a sequence partially complementary to the corresponding repeat and a unique portion;

co-folding of the tracrRNA with the pre-crRNA is essential for crRNA maturation and interference by the respective CRISPR–Cas systems. * Protospacer adjacent motif (PAM). A short,

two-to-three-nucleotide motif, the presence of which next to the protospacer sequence is essential for both adaptation and interference by most of the CRISPR–Cas systems; different PAM

sequences are required by different CRISPR-Cas types and subtypes. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Faure, G., Shmakov, S.A., Yan, W.X.

_et al._ CRISPR–Cas in mobile genetic elements: counter-defence and beyond. _Nat Rev Microbiol_ 17, 513–525 (2019). https://doi.org/10.1038/s41579-019-0204-7 Download citation * Published:

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