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

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.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Ranuncolo SM,Polo JM,Dierov J,Singer M,Kuo T,Greally J,Green R,Carroll M,Melnick A

doi

10.1038/ni1478

subject

Has Abstract

pub_date

2007-07-01 00:00:00

pages

705-14

issue

7

eissn

1529-2908

issn

1529-2916

pii

ni1478

journal_volume

8

pub_type

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