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 M. Greally, Roland Green, Martin Carroll, Ari Melnick

Research output: Contribution to journalArticle

180 Citations (Scopus)

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 2007
Externally publishedYes

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Germinal Center
DNA Damage
B-Lymphocytes
Phenotype
Antibody Diversity
Antibody Specificity
Genetic Recombination
Lymphoma
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. / Ranuncolo, Stella Maris; Polo, Jose M.; Dierov, Jamil; Singer, Michael; Kuo, Tracy; Greally, John M.; Green, Roland; Carroll, Martin; Melnick, Ari.

In: Nature Immunology, Vol. 8, No. 7, 07.2007, p. 705-714.

Research output: Contribution to journalArticle

Ranuncolo, Stella Maris ; Polo, Jose M. ; Dierov, Jamil ; Singer, Michael ; Kuo, Tracy ; Greally, John M. ; Green, Roland ; Carroll, Martin ; Melnick, Ari. / Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. In: Nature Immunology. 2007 ; Vol. 8, No. 7. pp. 705-714.
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