TitleBcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR.
Publication TypeJournal Article
Year of Publication2007
AuthorsRanuncolo, Stella Maris, Polo Jose M., Dierov Jamil, Singer Michael, Kuo Tracy, Greally John, Green Roland, Carroll Martin, and Melnick Ari
JournalNat Immunol
Date Published2007 Jul
KeywordsAtaxia Telangiectasia Mutated Proteins, B-Lymphocyte Subsets, Cell Cycle Proteins, Cell Line, Tumor, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Down-Regulation, Gene Silencing, Germinal Center, Humans, Immunophenotyping, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-6

<p>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.</p>

Alternate JournalNat Immunol
PubMed ID17558410
Grant ListR01 CA100885 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States