ArticleProceedings of the National Academy of Sciences of the United States of America2016
Real-time analysis of RAG complex activity in V(D)J recombination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
- Review
- The recombinase activating genes: architects of immune diversity during lymphocyte development.Frontiers in immunology · 2023Review
- Population matched (pm) germline allelic variants of immunoglobulin (IG) loci: Relevance in infectious diseases and vaccination studies in human populations.Genes and immunity · 2021Article
- HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence.Molecular systems biology · 2021Article
- Sequence-dependent dynamics of synthetic and endogenous RSSs in V(D)J recombination.Nucleic acids research · 2020Article
- V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation.Immunology · 2020Review
- Polymerase μ in non-homologous DNA end joining: importance of the order of arrival at a double-strand break in a purified system.Nucleic acids research · 2020Article
- The essential elements for the noncovalent association of two DNA ends during NHEJ synapsis.Nature communications · 2019Article
- A novelBlood · 2019Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Single-molecule FRET (smFRET) and single-molecule colocalization (smCL) assays have allowed us to observe the recombination-activating gene (RAG) complex reaction mechanism in real time. Our smFRET data have revealed distinct bending modes at recombination signal sequence (RSS)-conserved regions before nicking and synapsis. We show that high mobility group box 1 (HMGB1) acts as a cofactor in stabilizing conformational changes at the 12RSS heptamer and increasing RAG1/2 binding affinity for 23RSS. Using smCL analysis, we have quantitatively measured RAG1/2 dwell time on 12RSS, 23RSS, and non-RSS DNA, confirming a strict RSS molecular specificity that was enhanced in the presence of a partner RSS in solution. Our studies also provide single-molecule determination of rate constants that were previously only possible by indirect methods, allowing us to conclude that RAG binding, bending, and synapsis precede catalysis. Our real-time analysis offers insight into the requirements for RSS-RSS pairing, architecture of the synaptic complex, and dynamics of the paired RSS substrates. We show that the synaptic complex is extremely stable and that heptamer regions of the 12RSS and 23RSS substrates in the synaptic complex are closely associated in a stable conformational state, whereas nonamer regions are perpendicular. Our data provide an enhanced and comprehensive mechanistic description of the structural dynamics and associated enzyme kinetics of variable, diversity, and joining [V(D)J] recombination.
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