Article abstract
Nature Immunology 8, 705 - 714 (2007)
Published online: 10 June 2007 | doi:10.1038/ni1478
Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR
Stella Maris Ranuncolo1, Jose M Polo1, Jamil Dierov2, Michael Singer3, Tracy Kuo4, John Greally5, Roland Green3, Martin Carroll2 & Ari Melnick1
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.
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
- Hematology-Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
- NimbleGen Systems, Madison, Wisconsin 53711, USA.
- Department of Molecular and Cell Biology, Division of Immunology, University of California, Berkeley, California 94720, USA.
- Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Correspondence to: Martin Carroll2 e-mail: carroll2@mail.med.upenn.edu
Correspondence to: Ari Melnick1 e-mail: amelnick@aecom.yu.edu
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