Key Points
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HUH endonucleases contain the characteristic HUH motif (in which U represents a hydrophobic residue) and a Y motif, containing either one or two Tyr residues.
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HUH endonucleases catalyse breakage and joining of single-stranded DNA (ssDNA) by a unique mechanism using a Y motif Tyr to create a 5′ intermediate covalent bond with the ssDNA substrate.
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Many HUH endonucleases recognize and bind DNA hairpin structures in a sequence- or structure-specific way.
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Rep (replication) proteins are HUH endonucleases that mediate rolling circle replication in phages, plasmids and viruses.
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Relaxases use the HUH mechanism to catalyse plasmid replication and conjugation.
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Transposases are HUH endonucleases that mediate ssDNA transposition — for example, for the IS91 family and IS200–IS605 family insertion sequences, for insertion sequences with a common region (ISCRs) and for Helitrons.
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HUH endonucleases use the same catalytic motifs to mediate a diverse array of reactions, and this versatility has led to the widespread adoption of the HUH mechanism.
Abstract
HUH endonucleases are numerous and widespread in all three domains of life. The major function of these enzymes is processing a range of mobile genetic elements by catalysing cleavage and rejoining of single-stranded DNA using an active-site Tyr residue to make a transient 5′-phosphotyrosine bond with the DNA substrate. These enzymes have a key role in rolling-circle replication of plasmids and bacteriophages, in plasmid transfer, in the replication of several eukaryotic viruses and in various types of transposition. They have also been appropriated for cellular processes such as intron homing and the processing of bacterial repeated extragenic palindromes. Here, we provide an overview of these fascinating enzymes and their functions, using well-characterized examples of Rep proteins, relaxases and transposases, and we explore the molecular mechanisms used in their diverse activities.
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Acknowledgements
The authors thank C. Guynet, S. Messing and I. Molineau for discussions. This work was supported by intramural funding from the French Centre National de la Recherche Scientifique (to M.C. and B.T.H.) and the Intramural Program of the US National Institute of Diabetes and Digestive and Kidney Diseases (to A.B.H. and F.D.), and by grants from the French Agence National de Recherche (ANR-12-BSV8-0009-01; to B.T.H.), the Spanish Ministry of Science and Innovation (BIO2010-14809; to G.M.), the Spanish Ministry of Education (BFU2011-26608; to F.d.l.C.) and the European Seventh Framework Program (248919/FP7-ICT-2009-4 and 282004/FP7-HEALTH.2011.2.3.1-2; to F.d.l.C.).
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Major features of HUH enzymes (PDF 292 kb)
Glossary
- Repetitive extragenic palindromic sequences
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Abundant non-coding repeats that are found in bacterial genomes and form DNA hairpin structures that can have regulatory functions.
- Rolling-circle replication
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Unidirectional replication of circular DNA molecules (such as plasmids and phage genomes) in which a single-stranded product is 'peeled' from a circular DNA template.
- Insertion sequences with a common region
-
Insertion sequences that contain a common ORF which has similarity to the transposase ORF encoded in insertion sequence IS91. These elements seem to be able to sequester additional neighbouring genes during their transposition.
- Insertion sequences
-
Short transposable DNA segments that include one or more genes involved in their own mobility.
- Helitron
-
A type of eukaryotic transposon that is thought to transpose using a rolling-circle replication mechanism similar to that of insertion sequence IS91.
- Helicase
-
An enzyme that unwinds and separates double-stranded DNA. Helicases are classified into six major superfamilies (SF1–SF6) on the basis of the motifs and consensus sequences shared by the molecules and their activities (for example, 5′–3′ or 3′–5′ directionality).
- Type IV secretion system
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A multiprotein apparatus that is used by bacteria to transport both DNA and proteins across the bacterial cell envelope.
- Integrative and conjugative element
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A mobile genetic element that has the transfer properties of a conjugative plasmid but that is generally unable to replicate autonomously and possesses dedicated integration systems to allow the element to be maintained by integration into the host chromosome.
- DDE family transposase
-
A transposase that contains a characteristic DDE amino acid motif.
- R-loops
-
Regions of DNA in which the two strands are separated by a short RNA segment that forms a complementary RNA–DNA hybrid with one of the DNA strands.
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Chandler, M., de la Cruz, F., Dyda, F. et al. Breaking and joining single-stranded DNA: the HUH endonuclease superfamily. Nat Rev Microbiol 11, 525–538 (2013). https://doi.org/10.1038/nrmicro3067
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DOI: https://doi.org/10.1038/nrmicro3067
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Transposon-encoded nucleases use guide RNAs to promote their selfish spread
Nature (2023)
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Real-time visualisation of the intracellular dynamics of conjugative plasmid transfer
Nature Communications (2023)
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From parasites to partners: exploring the intricacies of host-transposon dynamics and coevolution
Functional & Integrative Genomics (2023)
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Amesuviridae: a new family of plant-infecting viruses in the phylum Cressdnaviricota, realm Monodnaviria
Archives of Virology (2023)
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Naryaviridae, Nenyaviridae, and Vilyaviridae: three new families of single-stranded DNA viruses in the phylum Cressdnaviricota
Archives of Virology (2022)