ArticleGenes & development1999
Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase.
Article in Genes & development, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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Who cites it
100 citing papers in PubMed, 196 citations in OpenAlex.
- A Naturally Active Spy Transposon Discovered from the Insect Genome of Colletes gigas as a Promising Novel Gene Transfer Tool.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- RAG genomic variation causes autoimmune diseases through specific structure-based mechanisms of enzyme dysregulation.iScience · 2023Article
- Comparison of immunophenotypes between Rag2 knockout mice derived from two different sources.Laboratory animal research · 2023Article
- Nuclease-independent functions of RAG1 direct distinct DNA damage responses in B cells.EMBO reports · 2023Article
- Engineered Sleeping Beauty transposase redirects transposon integration away from genes.Nucleic acids research · 2022Article
- Different sea urchin RAG-like genes were domesticated to carry out different functions.Frontiers in immunology · 2022Article
- RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination.Cell reports · 2021Article
- Templated insertions at VD and DJ junctions create unique B-cell receptors in the healthy B-cell repertoire.European journal of immunology · 2020Article
- A single amino acid switch converts the Sleeping Beauty transposase into an efficient unidirectional excisionase with utility in stem cell reprogramming.Nucleic acids research · 2020Article
- Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.Molecular cell · 2019Article
- RAG gene defects at the verge of immunodeficiency and immune dysregulation.Immunological reviews · 2019Review
- The ESC: The Dangerous By-Product of V(D)J Recombination.Frontiers in immunology · 2019Review
- Cracking the DNA Code for V(D)J Recombination.Molecular cell · 2018Article
- The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect.Cell reports · 2017Article
- New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination.The FEBS journal · 2017Review
- Human RAG mutations: biochemistry and clinical implications.Nature reviews. Immunology · 2016Review
- Recruitment of RAG1 and RAG2 to Chromatinized DNA during V(D)J Recombination.Molecular and cellular biology · 2015Article
- Retroviral Integrase: Then and Now.Annual review of virology · 2015Review
- Novel molecular mechanism for generating NK-cell fitness and memory.European journal of immunology · 2015Review
- Assembly Pathway and Characterization of the RAG1/2-DNA Paired and Signal-end Complexes.The Journal of biological chemistry · 2015Article
40 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.