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DNA melting initiates the RAG catalytic pathway.

<div class='caption-title'>Cryo-EM structure determination.</div>
<div class='caption-title'>Overview of cryo-EM maps and models.</div>
<div class='caption-title'>DNA distortion and active sites in the RNH domains for unmelted, melted and nicked RSSs.</div>
Ru H, Mi W, Zhang P, Alt FW, Schatz DG, Liao M, Wu H
OpenAccess logo Nat Struct Mol Biol 25 732-742 (2018)
Related entries: 6dbj, 6dbl, 6dbo, 6dbq, 6dbr, 6dbt, 6dbu, 6dbv, 6dbw, 6dbx

Cited: 32 times
EuropePMC logo PMID: 30061602

Abstract

The mechanism for initiating DNA cleavage by DDE-family enzymes, including the RAG endonuclease, which initiates V(D)J recombination, is not well understood. Here we report six cryo-EM structures of zebrafish RAG in complex with one or two intact recombination signal sequences (RSSs), at up to 3.9-Å resolution. Unexpectedly, these structures reveal DNA melting at the heptamer of the RSSs, thus resulting in a corkscrew-like rotation of coding-flank DNA and the positioning of the scissile phosphate in the active site. Substrate binding is associated with dimer opening and a piston-like movement in RAG1, first outward to accommodate unmelted DNA and then inward to wedge melted DNA. These precleavage complexes show limited base-specific contacts of RAG at the conserved terminal CAC/GTG sequence of the heptamer, thus suggesting conservation based on a propensity to unwind. CA and TG overwhelmingly dominate terminal sequences in transposons and retrotransposons, thereby implicating a universal mechanism for DNA melting during the initiation of retroviral integration and DNA transposition.

Reviews - 6dbi mentioned but not cited (3)

  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)
  2. Structural gymnastics of RAG-mediated DNA cleavage in V(D)J recombination. Ru H, Zhang P, Wu H. Curr Opin Struct Biol 53 178-186 (2018)
  3. 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 - 6dbi mentioned but not cited (3)

  1. DNA melting initiates the RAG catalytic pathway. Ru H, Mi W, Zhang P, Alt FW, Schatz DG, Liao M, Wu H. Nat Struct Mol Biol 25 732-742 (2018)
  2. research-article A new twist on V(D)J recombination. Dyda F, Rice PA. Nat Struct Mol Biol 25 648-649 (2018)
  3. Benchmark dataset for the Voronoi diagram of 3D spherical balls. Song C, Lee M, Choi S, Kim DS. Data Brief 45 108605 (2022)


Reviews citing this publication (9)

  1. The recent advances in non-homologous end-joining through the lens of lymphocyte development. Wang XS, Lee BJ, Zha S. DNA Repair (Amst) 94 102874 (2020)
  2. The role of chromatin loop extrusion in antibody diversification. Zhang Y, Zhang X, Dai HQ, Hu H, Alt FW. Nat Rev Immunol 22 550-566 (2022)
  3. Structural insights into the evolution of the RAG recombinase. Liu C, Zhang Y, Liu CC, Schatz DG. Nat Rev Immunol 22 353-370 (2022)
  4. Mechanism and regulation of P element transposition. Ghanim GE, Rio DC, Teixeira FK. Open Biol 10 200244 (2020)
  5. Read between the Lines: Diversity of Nontranslational Selection Pressures on Local Codon Usage. Callens M, Pradier L, Finnegan M, Rose C, Bedhomme S. Genome Biol Evol 13 evab097 (2021)
  6. The ESC: The Dangerous By-Product of V(D)J Recombination. Smith AL, Scott JNF, Boyes J. Front Immunol 10 1572 (2019)
  7. DNA Damage Response and Repair in Adaptive Immunity. Luo S, Qiao R, Zhang X. Front Cell Dev Biol 10 884873 (2022)
  8. Locus architecture and RAG scanning determine antibody diversity. Kenter AL, Priyadarshi S, Drake EB. Trends Immunol 44 119-128 (2023)
  9. Molecular Mechanisms of DNA Sequence Selectivity in V(D)J Recombination. Hoolehan W, Harris JC, Rodgers KK. ACS Omega 8 34206-34214 (2023)

Articles citing this publication (17)

  1. Transposon molecular domestication and the evolution of the RAG recombinase. Zhang Y, Cheng TC, Huang G, Lu Q, Surleac MD, Mandell JD, Pontarotti P, Petrescu AJ, Xu A, Xiong Y, Schatz DG. Nature 569 79-84 (2019)
  2. Structures of a RAG-like transposase during cut-and-paste transposition. Liu C, Yang Y, Schatz DG. Nature 575 540-544 (2019)
  3. 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)
  4. Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability. Kirkham CM, Scott JNF, Wang X, Smith AL, Kupinski AP, Ford AM, Westhead DR, Stockley PG, Tuma R, Boyes J. Mol Cell 74 584-597.e9 (2019)
  5. 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)
  6. Identification of RAG-like transposons in protostomes suggests their ancient bilaterian origin. Martin EC, Vicari C, Tsakou-Ngouafo L, Pontarotti P, Petrescu AJ, Schatz DG. Mob DNA 11 17 (2020)
  7. 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)
  8. 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)
  9. RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination. Gan T, Wang Y, Liu Y, Schatz DG, Hu J. Cell Rep 37 109824 (2021)
  10. Structural basis for the activation and suppression of transposition during evolution of the RAG recombinase. Zhang Y, Corbett E, Wu S, Schatz DG. EMBO J 39 e105857 (2020)
  11. Sequence-dependent dynamics of synthetic and endogenous RSSs in V(D)J recombination. Hirokawa S, Chure G, Belliveau NM, Lovely GA, Anaya M, Schatz DG, Baltimore D, Phillips R. Nucleic Acids Res 48 6726-6739 (2020)
  12. An updated definition of V(D)J recombination signal sequences revealed by high-throughput recombination assays. Hoolehan W, Harris JC, Byrum JN, Simpson DA, Rodgers KK. Nucleic Acids Res 50 11696-11711 (2022)
  13. Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations. Lugo-Reyes SO, Pastor N, González-Serrano E, Yamazaki-Nakashimada MA, Scheffler-Mendoza S, Berron-Ruiz L, Wakida G, Nuñez-Nuñez ME, Macias-Robles AP, Staines-Boone AT, Venegas-Montoya E, Alaez-Verson C, Molina-Garay C, Flores-Lagunes LL, Carrillo-Sanchez K, Niemela J, Rosenzweig SD, Gaytan P, Yañez JA, Martinez-Duncker I, Notarangelo LD, Espinosa-Padilla S, Cruz-Munoz ME. J Clin Immunol 41 1291-1302 (2021)
  14. Functional requirement of terminal inverted repeats for efficient ProtoRAG activity reveals the early evolution of V(D)J recombination. Tao X, Yuan S, Chen F, Gao X, Wang X, Yu W, Liu S, Huang Z, Chen S, Xu A. Natl Sci Rev 7 403-417 (2020)
  15. Genome-Wide Identification, Characterization, and Expression Analysis of DDE_Tnp_4 Family Genes in Eriocheir sinensis. Xu Y, Zheng J, Yang Y, Cui Z. Antibiotics (Basel) 10 1430 (2021)
  16. Germline DNA Retention in Murine and Human Rearranged T Cell Receptor Gene Coding Joints: Alternative Recombination Signal Sequences and V(D)J Recombinase Errors. Mika J, Kabacik S, Badie C, Polanska J, Candéias SM. Front Immunol 10 2637 (2019)
  17. Comment Snapshots of a genetic cut-and-paste. Barabas O. Nature 575 447-448 (2019)


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