Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Nat Immunol. 2007 Jul;8(7):705-14. doi: 10.1038/ni1478. Epub 2007 Jun 10.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • B-Lymphocyte Subsets / enzymology*
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / pathology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Damage / genetics*
  • DNA-Binding Proteins / physiology*
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Gene Silencing
  • Germinal Center / enzymology*
  • Germinal Center / immunology
  • Germinal Center / pathology
  • Humans
  • Immunophenotyping
  • Lymphoma, B-Cell / enzymology*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / pathology
  • Lymphoma, Large B-Cell, Diffuse / enzymology*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-bcl-6

Substances

  • BCL6 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE7673