生物谷报道： 研究人员在6月在线出版的《自然—免疫学》（Nature Immunology）期刊上报告说，一种通常与B细胞淋巴瘤相关的蛋白质抑制了对“有用”B细胞的消灭，否则，将隐含DNA损害的危机。
在绝大多数细胞中，DNA的损害将触发“感应器”中断细胞的活动，直至DNA的损害获得了修复。生发中心细胞能产生抗体，在一组选择出来的名为生发中心细胞的B细胞组中，Ari Melnick和同事发现蛋白质Bcl—6能阻止DNA损伤感应器ATR的产生。在这组B细胞中，Bcl—6有益于受到外来抗原侵袭，并在抗原编码的基因中经历DNA严重变异的B细胞，通常情况下，这一过程需要产生高效的抗体。然而，这种DNA变异却导致生发中心B细胞的死亡，从而间接减少了了有用抗体的产生。
Melnick小组的研究显示，Bcl—6能抑制ATR基因的活性，这种基因能有效地关闭DNA损害感应器的机制，导致生发中心B细胞不再倾向于DAN损失所引导的死亡。而且，许多B细胞淋巴瘤显示，解除管制的Bcl—6能表达和容忍过度的DNA变异，包括由辐射治疗引发的变异。
这项新研究推测，淋巴瘤细胞中Bcl—6的变异可能会让它们对辐射更敏感。(援引科学时报)
原始出处:
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
