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Structural insights into the mechanism of double strand break formation by Hermes, a hAT family eukaryotic DNA transposase.

Hickman AB, Voth AR, Ewis H, Li X, Craig NL, Dyda F
Nucleic Acids Res 46 10286-10301 (2018)
Related entries: 6dwy, 6dwz, 6dx0

Cited: 12 times
EuropePMC logo PMID: 30239795

Abstract

Some DNA transposons relocate from one genomic location to another using a mechanism that involves generating double-strand breaks at their transposon ends by forming hairpins on flanking DNA. The same double-strand break mode is employed by the V(D)J recombinase at signal-end/coding-end junctions during the generation of antibody diversity. How flanking hairpins are formed during DNA transposition has remained elusive. Here, we describe several co-crystal structures of the Hermes transposase bound to DNA that mimics the reaction step immediately prior to hairpin formation. Our results reveal a large DNA conformational change between the initial cleavage step and subsequent hairpin formation that changes which strand is acted upon by a single active site. We observed that two factors affect the conformational change: the complement of divalent metal ions bound by the catalytically essential DDE residues, and the identity of the -2 flanking base pair. Our data also provides a mechanistic link between the efficiency of hairpin formation (an A:T basepair is favored at the -2 position) and Hermes' strong target site preference. Furthermore, we have established that the histidine residue within a conserved C/DxxH motif present in many transposase families interacts directly with the scissile phosphate, suggesting a crucial role in catalysis.

Reviews - 6dww mentioned but not cited (1)

  1. Jump ahead with a twist: DNA acrobatics drive transposition forward. Arinkin V, Smyshlyaev G, Barabas O. Curr Opin Struct Biol 59 168-177 (2019)

Articles - 6dww mentioned but not cited (2)

  1. How mouse RAG recombinase avoids DNA transposition. Chen X, Cui Y, Wang H, Zhou ZH, Gellert M, Yang W. Nat Struct Mol Biol 27 127-133 (2020)
  2. Structural insights into the mechanism of double strand break formation by Hermes, a hAT family eukaryotic DNA transposase. Hickman AB, Voth AR, Ewis H, Li X, Craig NL, Dyda F. Nucleic Acids Res 46 10286-10301 (2018)


Reviews citing this publication (1)

  1. Inner workings of RAG recombinase and its specialization for adaptive immunity. Chen X, Gellert M, Yang W. Curr Opin Struct Biol 71 79-86 (2021)

Articles citing this publication (8)

  1. Structures of a RAG-like transposase during cut-and-paste transposition. Liu C, Yang Y, Schatz DG. Nature 575 540-544 (2019)
  2. Cutting antiparallel DNA strands in a single active site. Chen X, Cui Y, Best RB, Wang H, Zhou ZH, Yang W, Gellert M. Nat Struct Mol Biol 27 119-126 (2020)
  3. Structures of ISCth4 transpososomes reveal the role of asymmetry in copy-out/paste-in DNA transposition. Kosek D, Hickman AB, Ghirlando R, He S, Dyda F. EMBO J 40 e105666 (2021)
  4. Transposons to V(D)J Recombination: Evolution of the RAG Reaction. Lieber MR. Trends Immunol 40 668-670 (2019)
  5. Functional analysis of the catalytic triad of the hAT-family transposase TcBuster. Woodard LE, Williams FM, Jarrett IC, Wilson MH. Plasmid 114 102554 (2021)
  6. Massive Somatic and Germline Chromosomal Integrations of Polydnaviruses in Lepidopterans. Heisserer C, Muller H, Jouan V, Musset K, Periquet G, Drezen JM, Volkoff AN, Gilbert C. Mol Biol Evol 40 msad050 (2023)
  7. Comment Snapshots of a genetic cut-and-paste. Barabas O. Nature 575 447-448 (2019)
  8. Zinc-finger BED domains drive the formation of the active Hermes transpososome by asymmetric DNA binding. Lannes L, Furman CM, Hickman AB, Dyda F. Nat Commun 14 4470 (2023)


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