RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci

Hewitt, Susannah L.; Yin, Bu; Ji, Yanhong; Chaumeil, Julie; Marszalek, Katarzyna; Tenthorey, Jeannette; Salvagiotto, Giorgia; Steinel, Natalie C.; Ramsey, Laura B.; Ghysdael, Jacques; Farrar, Michael A.; Sleckman, Barry P.; Schatz, David G.; Busslinger, Meinrad; Bassing, Craig H.; Skok, Jane A.

doi:10.1038/ni.1735

Cited by 133 publications

(193 citation statements)

References 51 publications

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“…During early embryogenesis of female mammals, a transient somatic pairing has been shown to occur between homologous X chromosomes as part of the X inactivation process (Augui et al, 2007;Bacher et al, 2006;Xu et al, 2006). A temporary pairing of homologous immunoglobulin genes also occurs during the development of B cells and is associated with the subsequent monoallelic recombination and transcription of these loci (Hewitt et al, 2009). In the light of these findings, one appealing model is that separation of homologous chromosomes would allow for maintenance of two copies of monoallelically expressed genes at a distance, avoiding their co-regulation, whereas active mechanisms would dynamically control transient interchromosomal contacts required to set up this differential allelic expression.…”

Section: Discussionmentioning

confidence: 99%

Distance between homologous chromosomes results from chromosome positioning constraints

Heride

Ricoul

Kiêu

et al. 2010

Journal of Cell Science

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SummaryThe organization of chromosomes is important for various biological processes and is involved in the formation of rearrangements often observed in cancer. In mammals, chromosomes are organized in territories that are radially positioned in the nucleus. However, it remains unclear whether chromosomes are organized relative to each other. Here, we examine the nuclear arrangement of 10 chromosomes in human epithelial cancer cells by three-dimensional FISH analysis. We show that their radial position correlates with the ratio of their gene density to chromosome size. We also observe that inter-homologue distances are generally larger than interheterologue distances. Using numerical simulations taking radial position constraints into account, we demonstrate that, for some chromosomes, radial position is enough to justify the inter-homologue distance, whereas for others additional constraints are involved. Among these constraints, we propose that nucleolar organizer regions participate in the internal positioning of the acrocentric chromosome HSA21, possibly through interactions with nucleoli. Maintaining distance between homologous chromosomes in human cells could participate in regulating genome stability and gene expression, both mechanisms that are key players in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Distance between homologous chromosomes results from chromosome positioning constraints

Heride

Ricoul

Kiêu

et al. 2010

Journal of Cell Science

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“…DNA FISH-immunofluorescence for γ-H2AX was carried out on interphase nuclei of sorted DPs as in ref. 51. Labeled BAC probes RP23-255N13 (3′ end of the Tcra locus) and RP24-307D14 (Myc) were used.…”

Section: Methodsmentioning

confidence: 99%

β-Catenin induces T-cell transformation by promoting genomic instability

Dose

Emmanuel

Chaumeil

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Deregulated activation of β-catenin in cancer has been correlated with genomic instability. During thymocyte development, β-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human T-ALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated β-catenin promoted an antiapoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.beta-catenin/Tcf-1 | DNA recombination Tcf7 | Ctnnb1

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“…Therefore, V-to-DJ recombination must either be asynchronous to allow enough time for H chain surface expression and pre-BCR signaling, or a productive VDJ recombination event must halt recombination until pre-BCR signals have been initiated. Because the repair-checkpoint protein ATM is activated by recombination-induced DNA double-strand breaks, it is thought to play a role in this process (23). Afterward, both IgH loci are "decontracted" to suppress further V-to-DJ rearrangements, and the partially rearranged IgH allele is silenced by pericentromeric relocation, thereby making it inaccessible for Rag (21,22,(24)(25)(26)(27).…”

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confidence: 99%

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Lutz

Heideman

Roth

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro-B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized μH mRNA that does not encode μH chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that μH mRNA may thus contribute to efficient H chain allelic exclusion.

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RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci

Cited by 133 publications

References 51 publications

Distance between homologous chromosomes results from chromosome positioning constraints

Distance between homologous chromosomes results from chromosome positioning constraints

β-Catenin induces T-cell transformation by promoting genomic instability

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

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