Abstract
Antibody specificity and diversity is generated in B cells during germinal center maturation through clonal expansion while they undergo class-switch recombination and somatic hypermutation. Here we demonstrate that the transcriptional repressor Bcl-6 mediates this phenotype by directly repressing ATR in centroblasts and lymphoma cells. ATR is critical in replication and DNA damage-sensing checkpoints. Bcl-6 allowed B cells to evade ATR-mediated checkpoints and attenuated the response of the B cells to exogenous DNA damage. Repression of ATR was necessary and sufficient for those Bcl-6 activities. CD40 signaling 'rescued' B cells from those effects by disrupting the Bcl-6 transcription-repression complex on the promoter of the gene encoding ATR. Our data demonstrate a transcriptional regulatory loop whereby Bcl-6 mediates the centroblast phenotype through transient silencing of ATR.
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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Ataxia Telangiectasia Mutated Proteins
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B-Lymphocyte Subsets / enzymology*
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B-Lymphocyte Subsets / immunology
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B-Lymphocyte Subsets / pathology
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Line, Tumor
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Cells, Cultured
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DNA Damage / genetics*
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DNA-Binding Proteins / physiology*
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Down-Regulation / genetics
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Down-Regulation / immunology
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Gene Silencing
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Germinal Center / enzymology*
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Germinal Center / immunology
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Germinal Center / pathology
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Humans
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Immunophenotyping
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Lymphoma, B-Cell / enzymology*
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / pathology
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Lymphoma, Large B-Cell, Diffuse / enzymology*
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / pathology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins c-bcl-6
Substances
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BCL6 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-bcl-6
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases