生物谷報(bào)道： 研究人員在6月在線出版的《自然—免疫學(xué)》（Nature Immunology）期刊上報(bào)告說,，一種通常與B細(xì)胞淋巴瘤相關(guān)的蛋白質(zhì)抑制了對“有用”B細(xì)胞的消滅，否則,，將隱含DNA損害的危機(jī),。
在絕大多數(shù)細(xì)胞中，DNA的損害將觸發(fā)“感應(yīng)器”中斷細(xì)胞的活動(dòng),，直至DNA的損害獲得了修復(fù),。生發(fā)中心細(xì)胞能產(chǎn)生抗體，在一組選擇出來的名為生發(fā)中心細(xì)胞的B細(xì)胞組中,，Ari Melnick和同事發(fā)現(xiàn)蛋白質(zhì)Bcl—6能阻止DNA損傷感應(yīng)器ATR的產(chǎn)生,。在這組B細(xì)胞中,，Bcl—6有益于受到外來抗原侵襲，并在抗原編碼的基因中經(jīng)歷DNA嚴(yán)重變異的B細(xì)胞,，通常情況下,，這一過程需要產(chǎn)生高效的抗體。然而,，這種DNA變異卻導(dǎo)致生發(fā)中心B細(xì)胞的死亡,，從而間接減少了了有用抗體的產(chǎn)生。
Melnick小組的研究顯示,，Bcl—6能抑制ATR基因的活性,，這種基因能有效地關(guān)閉DNA損害感應(yīng)器的機(jī)制，導(dǎo)致生發(fā)中心B細(xì)胞不再傾向于DAN損失所引導(dǎo)的死亡,。而且,，許多B細(xì)胞淋巴瘤顯示，解除管制的Bcl—6能表達(dá)和容忍過度的DNA變異,，包括由輻射治療引發(fā)的變異,。
這項(xiàng)新研究推測，淋巴瘤細(xì)胞中Bcl—6的變異可能會(huì)讓它們對輻射更敏感,。(援引科學(xué)時(shí)報(bào))
原始出處:
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: [email protected]
Correspondence to: Ari Melnick1 e-mail: [email protected]
