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

Overview

MeSH Major

  • B-Lymphocyte Subsets
  • Cell Cycle Proteins
  • DNA Damage
  • DNA-Binding Proteins
  • Germinal Center
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse
  • Protein-Serine-Threonine Kinases

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 date

  • July 2007

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1038/ni1478

PubMed ID

  • 17558410

Additional Document Info

start page

  • 705

end page

  • 14

volume

  • 8

number

  • 7