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

被引:205
作者
Ranuncolo, Stella Maris
Polo, Jose M.
Dierov, Jamil
Singer, Michael
Kuo, Tracy
Greally, John
Green, Roland
Carroll, Martin [1 ]
Melnick, Ari
机构
[1] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA
[2] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA
[3] NimbleGen Syst, Madison, WI 53711 USA
[4] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol, Berkeley, CA 94720 USA
[5] Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA
关键词
CLASS SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; DEAMINASE AID; ACTIVATION; EXPRESSION; REPLICATION; HYPERMUTATION; CHECKPOINT; DIFFERENTIATION; INFLAMMATION;
D O I
10.1038/ni1478
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:705 / 714
页数:10
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