title: 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.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Stella Maris
authors.initials: SM
authors.lastname: Ranuncolo
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.forename: Jamil
authors.initials: J
authors.lastname: Dierov
authors.forename: Michael
authors.initials: M
authors.lastname: Singer
authors.forename: Tracy
authors.initials: T
authors.lastname: Kuo
authors.forename: John
authors.initials: J
authors.lastname: Greally
authors.forename: Roland
authors.initials: R
authors.lastname: Green
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: 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
chemical_list: 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