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Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase
Open accessAbstract
The RAG1 and RAG2 proteins collaborate to initiate V(D)J recombination by binding recombination signal sequences (RSSs) and making a double-strand break between the RSS and adjacent coding DNA. Like the reactions of their biochemical cousins, the bacterial transposases and retroviral integrases, cleavage by the RAG proteins requires a divalent metal ion but does not involve a covalent protein/DNA intermediate. In the transposase/integrase family, a triplet of acidic residues, commonly called a DDE motif, is often found to coordinate the metal ion used for catalysis. We show here that mutations in each of three acidic residues in RAG1 result in mutant derivatives that can bind the RSS but whose ability to catalyze either of the two chemical steps of V(D)J cleavage (nicking and hairpin formation) is severely impaired. Because both chemical steps are affected by the same mutations, a single active site appears responsible for both reactions. Two independent lines of evidence demonstrate that at least two of these acidic residues are directly involved in coordinating a divalent metal ion: The substitution of Cys for Asp allows rescue of some catalytic function, whereas an alanine substitution is no longer subject to iron-induced hydroxyl radical cleavage. Our results support a model in which the RAG1 protein contains the active site of the V(D)J recombinase and are interpreted in light of predictions about the structure of RAG1.
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“All three core residues from the catalytic DDE triad in the RAG1 proteins (residues 603, 711, and 965) that are necessary for V(D)J recombination [21,22] are conserved in the Transib TPases (Figures 3 and Figure S3).”
From RAG1 Core and V(D)J Recombination Signal Sequences Were Derived from Transib Transposons (2005) · cites this paper as [21]
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“The mouse core RAG1/2 (wild-type or E962Q mutant RAG1 aa 384-1008 and RAG2 aa 1-359, tRAG1/2 (RAG1 aa 459-1008) and extended RAG1/2 (RAG1 aa 265-1040 and RAG2 aa 1-520 with a T490A mutation) proteins were expressed as N-terminal His6MBP fusions in HEK293T cells and purified as previously described (Kim et al., 2015),…”
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“Although three active-site residues, D600, D708, and E962, are required for both nicking and hairpin formation (16, 30, 33), each of these steps is likely to also involve some distinct active-site amino acids.”
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“…are many functional similarities between the RAG the target DNA) distinguish this reaction from the non- proteins and other transposases (including the presence specific RAG flap endonuclease recently described of a DDE motif of active site residues) (Kim et al., 1999; (Santagata et al., 1999).”
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“The active core of RAG1-RAG2 is defined by three acidic amino acid residues that lie in a region of RAG1 whose predicted secondary structure is similar to the secondary structure observed in the crystal structures of the catalytic cores of a host of transposases and retroviral integrases (18, 26, 28).”
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“Both Tn5 and Tn10 transpositions share additional features with V(D)J recombination, including (i) the generation of DNA hairpin intermediates (6, 19); (ii) the presence of a single enzyme binding site at each DNA end undergoing cleavage (21, 34); (iii) an unusually large spacing between the second Asp and third Glu r…”
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“The RAG1 core contains the DDE triad that is found in many ‘‘cut and paste’’ DNA transposases (Fugmann et al., 2000; Kim et al., 1999; Landree et al., 1999).”
Self-citationATP-dependent Remodeling by SWI/SNF and ISWI Proteins Stimulates V(D)J Cleavage of 5 S Arrays
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Self-citationCooperative recruitment of HMGB1 during V(D)J recombination through interactions with RAG1 and DNA
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Gene therapy vectors: the prospects and potentials of the cut-and-paste transposons
Bouuaert, C. C., & Chalmers, R. (2009) · Genetica · doi:10.1007/s10709-009-9391-x · Cited by 46
“However, only the first nick is completed as the hairpin step is coupled to synapsis by conformational changes in the complex (West and Lieber 1998; Kim et al. 1999; Yu and Lieber 2000).”
BackgroundEffect of HIV integrase inhibitors on the RAG1/2 recombinase
Melek, M., Jones, J. M., O'Dea, M. H., Pais, G. C. G., Burke, T. R., Pommier, Y. G., Neamati, N., & Gellert, M. F. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012610699 · Cited by 46
Artemis sheds new light on V(D)J recombination
Deist, F. L., Poinsignon, C., Moshous, D., Fischer, A., & de Villartay, J. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00169.x · Cited by 45
Keith, J. H., Schaeper, C. A., Fraser, T. S., & Fraser, M. J. (2008) · BMC Molecular Biology · doi:10.1186/1471-2199-9-73 · Cited by 44
“Regarding recombinases, this approach was used to narrow down the location of the metal binding residues of RAG1 prior to the generation of site-specific mutants [43].”
BackgroundMethodIdentification and Analysis of a Hyperactive Mutant Form of Drosophila P-Element Transposase
Beall, E. L., Mahoney, M. B., & Rio, D. C. (2002) · Genetics · doi:10.1093/genetics/162.1.217 · Cited by 40
Chaumeil, J., Micsinai, M., Ntziachristos, P., Deriano, L., Wang, J. M.-H., Ji, Y., Nora, E. P., Rodesch, M. J., Jeddeloh, J. A., Aifantis, I., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.024 · Cited by 44
“As a complementary control, we also included DP cells from D708A-R1 b mice, which, in addition to the Tcrb transgene, carry another transgene expressing a catalytically inactive version of the RAG1 protein that has a D708A active site substitution preventing DNA cleavage without impairing binding and synapsis of RSSs…”
BackgroundThe RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage
Chaumeil, J., Micsinai, M., Ntziachristos, P., Roth, D. B., Aifantis, I., Kluger, Y., Deriano, L., & Skok, J. A. (2013) · Nature Communications · doi:10.1038/ncomms3231 · Cited by 42
Temporal and spatial regulatory functions of the V(D)J recombinase
Desiderio, S. V. (2010) · Seminars in Immunology · doi:10.1016/j.smim.2010.09.001 · Cited by 42
“[6] Kim DR, Dai Y, Mundy CL, Yang W, Oettinger MA.”
BackgroundPeak, M. M., Arbuckle, J. L., & Rodgers, K. K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302041200 · Cited by 39
Ross, A. E., Vuica, M., & Desiderio, S. V. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5308-5319.2003 · Cited by 39
“nine substitutions over the intervals 489 to 498, 499 to 508, and 509 to 518 were distributed between the nucleus and the cytoplasm, as was observed for GFP-RAG-2(1-387) and GFPRAG-2(1-498) (Fig.”
BackgroundResultInfluentialAmino acid residues in Rag1 crucial for DNA hairpin formation
Lu, C. P.-J., Sandoval, H., Brandt, V. L., Rice, P. A., & Roth, D. B. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1154 · Cited by 38
“Biochemical and genetic studies have also revealed a catalytic DDE triad in Rag1 (refs”
BackgroundA C-Terminal Region of RAG1 Contacts the Coding DNA during V(D)J Recombination
Mo, X., Tu, B., & Sadofsky, M. J. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.6.2038-2047.2001 · Cited by 37
“This region includes the critical acidic residue E962 that has been proposed to represent part of the enzymatic active site (19, 21).”
BackgroundBryant, K. F., Yan, Z., Dreyfus, D. H., & Knipe, D. M. (2012) · Journal of Virology · doi:10.1128/jvi.00374-12 · Cited by 35
“The iron-induced protein cleavage assay was performed essentially as described previously (19).”
BackgroundMethodInfluentialRAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination
Gan, T., Wang, Y., Liu, Y., Schatz, D. G., & Hu, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109824 · Cited by 37
Coordination of Divalent Metal Ions in the Active Site of Poly(A)-specific Ribonuclease
Ren, Y.-G., Kirsebom, L. A., & Virtanen, A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403858200 · Cited by 35
RAG1 and RAG2 in V(D)J Recombination and Transposition
Fugmann, S. D. (2001) · Immunologic Research · doi:10.1385/ir:23:1:23 · Cited by 34
Couëdel, C., Roman, C. A. J., Jones, A., Vezzoni, P., VILLA, A. M., & Cortés, P. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41305 · Cited by 34
Gellert, M. F. (2007) · Wiley eBooks · doi:10.1128/9781555817954.ch29 · Cited by 33
Recombination‐activating gene proteins: more regulation, please
Sadofsky, M. J. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00164.x · Cited by 31
“All of the acidic residues believed to contribute to metal binding at the catalytic active-site reside on RAG1 (36, 37).”
BackgroundA recombinase diversified: new functions of the RAG proteins
Brandt, V. L., & Roth, D. B. (2002) · Current Opinion in Immunology · doi:10.1016/s0952-7915(02)00325-4 · Cited by 31
Conditional RAG-1 Mutants Block the Hairpin Formation Step of V(D)J Recombination
Kale, S. B., Landree, M. A., & Roth, D. B. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.2.459-466.2001 · Cited by 31
Wilson, D. R., Norton, D. D., & Fugmann, S. D. (2008) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2008.03.012 · Cited by 30
RAG and HMGB1 create a large bend in the 23RSS in the V(D)J recombination synaptic complexes
Ciubotaru, M., Trexler, A., Spiridon, L. N., Surleac, M. D., Rhoades, E. R., Petrescu, A., & Schatz, D. G. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks1294 · Cited by 30
“4%; Figure 4, bar 6), a mutant that supports SC and PC formation but no catalysis (21,34,35).”
BackgroundEngineered Sleeping Beauty transposase redirects transposon integration away from genes
Miskey, C., Kesselring, L., Querques, I., Abrusán, G., Barábas, O., & Ivics, Z. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac092 · Cited by 29
“Transposases (5–7), INs (8) and the RAG1 immunoglobulin gene recombinase (9, 10) all share an evolutionarily related catalytic domain, harboring a triad of negatively charged amino acids, the aspartate-aspartateglutamate/aspartate (DDE/D) motif.”
Arnal, S. M., Holub, A. J., Salus, S. S., & Roth, D. B. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkp1252 · Cited by 29
“The DDE mutant (D600A/D708A/E962A) is a catalytically inactive RAG1 mutant used as a control (38,39).”
MethodCut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability
Kirkham, C. M., Scott, J. N. F., Wang, X., Smith, A., Kupinski, A. P., Ford, A. M., Westhead, D. R., Stockley, P. G., Tůma, R., & Boyes, J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.025 · Cited by 29
“RAG1 binds to the RSS nonamer and following capture of a partner RSS to form a synaptic complex, RAG2 directs the RAG1 DDE catalytic site (Fugmann et al., 2000; Kim et al., 1999; Landree et al., 1999) to cleave the partner RSS precisely at the boundary between the heptamer and coding sequence (Kim et al.”
BackgroundInfluentialV(D)J Recombination: Site-specific Cleavage and Repair
Kim, D. R., Park, S. J., & Oettinger, M. A. (2000) · Molecules and Cells · doi:10.1016/s1016-8478(23)17488-7 · Cited by 29
Self-citation
Metadata
- Authors
- Kim, D. R., Dai, Y., Mundy, C. L., Yang, W., & Oettinger, M. A.
- Affiliations
- National Institutes of Health (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-12-01
- Volume
- 13
- Issue
- 23
- Pages
- 3070-3080
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC317176
- OpenAlex
- W1984676925
- Cited by
- 199
- References
- 52
- Citations by year
- 2024: 4 · 2023: 5 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 16 · 2014: 8 · 2013: 6 · 2012: 6
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- National Institutes of Health
- National Institute of General Medical Sciences (GM58026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- RAG1, RAG2, V(D)J recombination, recombination signal sequences, acidic residues, active site, nicking, hairpin formation, immunoglobulin gene rearrangement
- MeSH terms
- Amino Acid Sequence, Animals, Aspartic Acid, Binding Sites, DNA Nucleotidyltransferases, DNA-Binding Proteins, HeLa Cells, Humans, Iron, Manganese, Molecular Sequence Data, Nuclear Proteins, Phenotype, Protein Binding, Recombinant Fusion Proteins, Structure-Activity Relationship, Gene Rearrangement, Mutagenesis, Site-Directed, Protein Structure, Secondary, Protein Structure, Tertiary, Hydroxyl Radical, Homeodomain Proteins, Amino Acid Substitution, Catalytic Domain, VDJ Recombinases, Mice
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