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

Stella Maris Ranuncolo, Jose M. Polo, Jamil Dierov, Michael Singer, Tracy Kuo, John Greally, Roland Green, Martin Carroll, Ari Melnick

Research output: Contribution to journalArticle

184 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)705-714
Number of pages10
JournalNature Immunology
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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