Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR.
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.
Ranuncolo
Stella Maris
SM
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Polo
Jose M
JM
Dierov
Jamil
J
Singer
Michael
M
Kuo
Tracy
T
Greally
John
J
Green
Roland
R
Carroll
Martin
M
Melnick
Ari
A
D064007:Ataxia Telangiectasia Mutated Proteins; D016175:B-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020868:Gene Silencing; D018858:Germinal Center / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6
C084103:BCL6 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases