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NSMB:Mre11基因与抗体类别转换重组关系及致癌性

来源:生物谷 2009-08-14 15:29

MRN复合物是由三个蛋白质组成的基因修复复合体,这个复合体包括MRE11、Nbs1、Rad50三种蛋白质。MRN复合物在DNA双链损伤修复、同源重组、非同源重组、端粒长度维持、细胞检验点激活、保证DNA复制的顺利进行,以及维持基因组的稳定性等方面都起到了重要的作用。

当MRN复合物中的Mre11蛋白缺失时,会造成B细胞中DNA断裂修复机制出现错误。这一过程称为抗体类别转换重组(immunoglobulin class switch recombination)。DNA修复错误会改变B细胞功能,分泌不同抗体抵御病原体入侵机体。抗体类别转换重组在免疫系统清除病原体时起到重要作用,但是同样可能引起细胞癌变。

最近研究人员通过使用只有B细胞内Mre11基因突变的小鼠作为模型,发现Mre11基因缺陷会使染色体破坏,当DNA破坏位置处于免疫球蛋白基因里面时,抗体类别转换重组现象会出现。实验证明Mre11基因与DNA损伤修复有重要联系,而且可能在癌症预防方面也有关键作用。免疫球蛋白基因断裂后,可能会与基因组中远端基因重组,导致染色体易位造成癌症。Mre11基因保持正常活性时可以使B细胞DNA双链断裂得到有效修复,保证免疫系统正常工作。(生物谷Bioon.com)

生物谷推荐原始出处:

Nature Structural & Molecular Biology 16, 808 - 813 (2009) 26 July 2009 | doi:10.1038/nsmb.1639

Multiple functions of MRN in end-joining pathways during isotype class switching

Maria Dinkelmann1,3, Elizabeth Spehalski1,3, Trina Stoneham1, Jeffrey Buis1, Yipin Wu1, JoAnn M Sekiguchi2 & David O Ferguson1

The Mre11–Rad50–NBS1 (MRN) complex has many roles in response to DNA double-strand breaks, but its functions in repair by nonhomologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in class switch recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end, we have engineered mice that lack the entire MRN complex in B lymphocytes or that possess an intact complex that harbors mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a strong defect in CSR, affecting both the classic and the alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways.

1 Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
2 Departments of Internal Medicine and Human Genetics, The University of Michigan, Ann Arbor, Michigan, USA.
3 These authors contributed equally to this work.

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