Abstract
DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre-BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Here, we show that RAG DSBs inhibit pre-BCR signals through the ATM- and NF-κB2-dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre-BCR signaling. This regulatory circuit prevents the pre-BCR from inducing additional Igl chain gene rearrangements and driving pre-B cells with RAG DSBs into cycle. We propose that pre-B cells toggle between pre-BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes.
© 2016 Bednarski et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Ataxia Telangiectasia Mutated Proteins / deficiency
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Ataxia Telangiectasia Mutated Proteins / genetics
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Ataxia Telangiectasia Mutated Proteins / metabolism
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Cell Cycle Checkpoints / immunology
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Cell Proliferation
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DNA Breaks, Double-Stranded*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Rearrangement, B-Lymphocyte, Light Chain
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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NF-kappa B p52 Subunit / deficiency
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NF-kappa B p52 Subunit / genetics
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NF-kappa B p52 Subunit / metabolism
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NF-kappaB-Inducing Kinase
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Pre-B Cell Receptors / metabolism*
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Precursor Cells, B-Lymphoid / cytology
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Precursor Cells, B-Lymphoid / immunology*
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Precursor Cells, B-Lymphoid / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Signal Transduction / immunology
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Syk Kinase
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Trans-Activators / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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B cell linker protein
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DNA-Binding Proteins
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B p52 Subunit
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Nfkb2 protein, mouse
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Pre-B Cell Receptors
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Proto-Oncogene Proteins
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Spic protein, mouse
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Trans-Activators
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proto-oncogene protein Spi-1
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RAG-1 protein
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases