Recombination‐activating gene proteins: more regulation, please

@article{Sadofsky2004RecombinationactivatingGP,
  title={Recombination‐activating gene proteins: more regulation, please},
  author={Moshe J. Sadofsky},
  journal={Immunological Reviews},
  year={2004},
  volume={200}
}
  • M. Sadofsky
  • Published 1 August 2004
  • Biology
  • Immunological Reviews
Summary:  Developing B and T cells assemble gene segments in order to create the variable regions of immunoglobulin and T‐cell receptors required by our adaptive immune response. The chemistry of this recombination pathway requires a specific nuclease and a more general repair pathway for double‐strand breaks. A complex of the recombination‐activating gene 1 (RAG1) and RAG2 proteins provides the nuclease activity. In fact, RAG1 and RAG2 probably coordinate many steps involving the coding and… 
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27 Citations

Non-canonical roles for RAG1 in lymphocyte development
TLDR
The data presented in this thesis demonstrate that RAG1 has critical functions outside of V(D)J recombination that enhance AgR gene segment accessibility, promote V( D) J recombination at multiple AgR loci, and transduce pro-survival signals during AgR recombination to establish a broad AgR repertoire and thereby foster normal lymphocyte development.
Activation of 12/23-RSS-dependent RAG cleavage by hSWI/SNF complex in the absence of transcription.
Mobilization of RAG-Generated Signal Ends by Transposition and Insertion In Vivo
TLDR
An episome-based assay to detect products of RAG-mediated transposition in the human embryonic kidney cell line 293T failed to detect bona fide transposition events but instead yielded chromosome deletion and translocation events involving the signal end fragment mobilized by the RAG proteins.
SUMO Modification of Human XRCC4 Regulates Its Localization and Function in DNA Double-Strand Break Repair
TLDR
It is reported that human XRCC4 (for X-ray cross-complementation group 4), a protein essential for NHEJ, is subject to posttranslational protein modification, and genetic fusion of the SUMO sequence to the C terminus of the mutant restores nuclear localization and radiation resistance.
Noncore RAG1 Regions Promote Vβ Rearrangements and αβ T Cell Development by Overcoming Inherent Inefficiency of Vβ Recombination Signal Sequences
TLDR
The data indicate that noncore RAG1 regions establish a diverse TCR repertoire by overcoming Vβ RSS inefficiency to promote Vβ recombination and αβ T cell development, and by modulating TCRβ and TCRα gene segment utilization.
The structure-specific nicking of small heteroduplexes by the RAG complex: implications for lymphoid chromosomal translocations.
Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus.
TLDR
Advances that have been made in understanding how V(D)J recombination at the IgH locus is controlled are summarized and important areas for future investigation are discussed.
Cytosines, but Not Purines, Determine Recombination Activating Gene (RAG)-induced Breaks on Heteroduplex DNA Structures
TLDR
The mechanism of RAG cleavage described here could explain facets of chromosomal rearrangements specific to lymphoid tissues leading to genomic instability.
Differential reaction kinetics, cleavage complex formation, and nonamer binding domain dependence dictate the structure-specific and sequence-specific nuclease activity of RAGs.
Evidence for an ancient bilaterian origin of the RAG-like transposon
TLDR
The findings indicate that the RAGL transposon arose earlier in evolution than previously thought, either in an early bilaterian or prior to the divergence of bilaterians and non-bilaterians, and alter the understanding of the evolutionary history of this importanttransposon family.
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References

SHOWING 1-10 OF 76 REFERENCES
V(D)J recombination: RAG proteins, repair factors, and regulation.
  • M. Gellert
  • Biology
    Annual review of biochemistry
  • 2002
TLDR
V(D)J recombination is strongly regulated by limiting access to RSS sites within chromatin, so that particular sites are available only in certain cell types and developmental stages, and the roles of enhancers, histone acetylation, and chromatin remodeling factors in controlling accessibility are discussed.
Expression and V(D)J recombination activity of mutated RAG-1 proteins.
TLDR
The sequences encoding mouse RAG-1 are explored by deleting large parts of the gene and by introducing local sequence changes and it is found that a R AG-1 gene with 40% of the coding region deleted still retains its recombination function.
The C‐terminal portion of RAG2 protects against transposition in vitro
TLDR
It is shown that the full‐length RAG1 and RAG2 proteins alone can catalyze this reaction in vitro, and one role of this non‐catalytic domain may be to prevent transposition in developing lymphoid cells.
Dual role of RAG2 in V(D)J recombination: catalysis and regulation of ordered Ig gene assembly
TLDR
It is shown that the C‐terminus of the RAG2 protein, although dispensable for the basic recombination reaction and for Ig heavy chain DH to JH joining, is essential for efficient VH to DJH rearrangement at the IgH locus.
DNA-Rag Protein Interactions in the Control of Selective D Gene Utilization in the TCRβ Locus1
TLDR
It is proposed that selective gene segment usage is controlled at the level of differential assembly and/or stability of synaptic RS complexes, and that evolutionary “deterioration” of the RS motifs may have been important to allow the VDJ recombinase to exert autonomous control over gene segment use during gene rearrangement.
A basic motif in the N-terminal region of RAG1 enhances V(D)J recombination activity
TLDR
Using extrachromosomal recombination substrates, it is demonstrated here that the N-terminal region enhances the recombination activity of RAG1 by up to an order of magnitude in a variety of cell lines.
Dispensable sequence motifs in the RAG-1 and RAG-2 genes for plasmid V(D)J recombination.
TLDR
The results indicate that the N-terminal one-third of RAG-1, including a zinc-finger-like domain, and an acidic domain of R AG-2 are dispensable for activating V(D)J recombination in a fibroblast, although they contribute quantitatively.
Deletion of the RAG2 C terminus leads to impaired lymphoid development in mice
TLDR
It is shown that core RAG2 mice display a reduction in the total number of B and T cells, reflecting impaired lymphocyte development at the progenitor stage associated with reduced chromosomal V(D)J recombination.
The RAG proteins in V(D)J recombination: more than just a nuclease.
TLDR
RAG1 and RAG2 together form the nuclease that cleaves the DNA at the border of the signal sequences and additional roles of these proteins in organizing the reaction complex for subsequent steps are explored.
Definition of a core region of RAG-2 that is functional in V(D)J recombination.
TLDR
This work constructed mutated RAG-2 genes and examined their ability to support recombination of plasmid substrates in a fibroblast cell line and found that all basic features of V(D)J joining are retained in a R AG-2 protein with only the first 75% of the sequence.
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