RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Bednarski, Jeffrey J.; Pandey, R.; Schulte, Emily; White, Lynn S.; Chen, Bo-Ruei; Sandoval, Gabriel J.; Kohyama, Masanori; Haldar, Malay; Nickless, Andrew; Trott, Amanda; Cheng, Genhong; Murphy, Kenneth M.; Bassing, Craig H.; Payton, Jacqueline E.; Sleckman, Barry P.

doi:10.1084/jem.20151048

Cited by 45 publications

(77 citation statements)

References 57 publications

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“…The Sleckman laboratory recently reported a locus-specific trans -factor for RAG DSB-induced feedback inhibition of Igκ recombination that functions by downregulating transcription-linked accessibility of Jκ gene segments to the RAG endonuclease (27). In this context, the ability of etoposide to inhibit Igκ recombination could be due to downregulation of Rag1 and Rag2 expression and/or Jκ recombinational accessibility.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with this idea, we showed that mice lacking ATM develop higher than normal frequencies of lymphocytes with bi-allelic expression and/or translocations of Igκ, IgH, or TCRβ loci (26). The Sleckman lab found that RAG DSBs induced at one Igκ allele signal via ATM to activate expression of the hematopoietic-specific SpiC transcriptional repressor (27). SpiC inhibits RAG cleavage of the other Igκ allele by suppressing transcription-linked accessibility of Jκ gene segments to the RAG endonuclease (27).…”

Section: Introductionmentioning

confidence: 99%

“…The Sleckman lab found that RAG DSBs induced at one Igκ allele signal via ATM to activate expression of the hematopoietic-specific SpiC transcriptional repressor (27). SpiC inhibits RAG cleavage of the other Igκ allele by suppressing transcription-linked accessibility of Jκ gene segments to the RAG endonuclease (27). This body of work established the concept of DSB-induced feedback inhibition of Igκ recombination by RAG cleavage and demonstrated that this regulation involves ATM-dependent DDR signaling pathways that repress RAG expression and Igκ recombination potential.…”

Section: Introductionmentioning

confidence: 99%

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Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks

Fisher

Rivera-Reyes

Bloch

et al. 2017

The Journal of Immunology

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Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ATM kinase to feedback inhibit RAG expression and RAG cleavage of the other Igκ allele. Here, we show that DSBs induced by ionizing radiation, etoposide, or bleomycin suppress Rag1 and Rag2 mRNA levels in primary pre-B cells, pro-B cells, and pro-T cells, indicating that inhibition of Rag1 and Rag2 expression is a prevalent DSB response among immature lymphocytes. DSBs induced in pre-B cells signal rapid transcriptional repression of Rag1 and Rag2, causing downregulation of both Rag1 and Rag2 mRNA but only Rag1 protein. This transcriptional inhibition requires the ATM kinase and the NF-κB essential modulator protein, implicating a role for ATM-mediated activation of canonical NF-κB transcription factors. Finally, we demonstrate that DSBs induced in pre-B cells by etoposide or bleomycin inhibit recombination of Igκ loci and a chromosomally integrated substrate. Our data indicate that immature lymphocytes exploit a common DDR signaling pathway to limit DSBs at multiple genomic locations within developmental stages wherein monoallelic antigen receptor locus recombination is enforced. We discuss the implications of our findings for mechanisms that orchestrate the differentiation of mono-specific lymphocytes while suppressing oncogenic antigen receptor locus translocations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks

Fisher

Rivera-Reyes

Bloch

et al. 2017

The Journal of Immunology

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“…One notable target is the transcription factor SpiC, which is highly expressed by iron-recycling macrophages in the spleen (RPM) and is required for their development (3). SpiC is a member of the Spi subfamily of Ets transcription factor, which is also expressed in B cells (45, 46). High levels of heme in splenic red pulp were found to induce degradation of Bach1 protein in monocytes.…”

Section: Heme-mediated Regulation Of Iron-recycling Macrophagesmentioning

confidence: 99%

The Heme Connection: Linking Erythrocytes and Macrophage Biology

2017

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Erythroid function and development is intimately linked to macrophages. The primary function of erythrocytes is oxygen delivery, which is mediated by iron-containing hemoglobin. The major source of this iron is a recycling pathway where macrophages scavenge old and damaged erythrocytes to release iron contained within the heme moiety. Macrophages also promote erythropoiesis by providing a supportive niche in the bone marrow as an integral component of “erythorblastic islands.” Importantly, inflammation leads to alterations in iron handling by macrophages with significant impact on iron homeostasis and erythropoiesis. The importance of macrophages in erythropoiesis and iron homeostasis is well established and has been extensively reviewed. However, this developmental relationship is not one way, and erythrocytes can also regulate macrophage development and function. Erythrocyte-derived heme can induce the development of iron-recycling macrophages from monocytes, engage pattern recognition receptors to activate macrophages, and act as ligand for specific nuclear receptors to modulate macrophage function. Here, we discuss the role of heme as a signaling molecule impacting macrophage homeostasis. We will review these actions of heme within the framework of our current understanding of the role of micro-environmental factors in macrophage development and function.

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“…Additionally another study investigated whether RAG DSB-induced feedback inhibition might prevent V(D)J recombination through mechanisms in addition to down-regulation of RAG [51]. This study found that RAG Igκ DSBs induced in pre-B cells trigger ATM-dependent increases in the expression of RELB and NFκB2, which are non-canonical NFκB transcription factors.…”

Section: Rag Dsbs Signal Feedback Inhibition Of V(d)j Recombinationmentioning

confidence: 99%

V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity

Arya

Bassing

2017

Trends in Genetics

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It has been recognized for 40 years that V(D)J recombination-mediated assembly of diverse B and T lymphocyte antigen receptor genes is essential for adaptive immunity, yet also a risk for autoimmunity and lymphoid malignancies. In the past few years, several studies have revealed that RAG endonuclease-induced DNA double strand breaks (DSBs) transcend hazardous intermediates during antigen receptor gene assembly. RAG cleavage within the genomes of lymphocyte progenitors and immature lymphocytes regulates the expression of ubiquitous and lymphocyte-specific gene transcripts to control the differentiation and function of both adaptive and innate immune cell lineages. These unexpected discoveries raise important new questions that have broad implications for basic immunology research and the screening, diagnosis, and treatment of human immunological disease.

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RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Abstract: B-lineage cells reconcile the competing needs of proliferation and genome stability.

Cited by 45 publications

References 57 publications

Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks

Immature Lymphocytes Inhibit Rag1 and Rag2 Transcription and V(D)J Recombination in Response to DNA Double-Strand Breaks

The Heme Connection: Linking Erythrocytes and Macrophage Biology

V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity

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