由AID引发的DNA断裂的定向特定连接促进了抗体类别的切换
Junchao Dong1, Rohit A Panchakshari1, Tingting Zhang1
1Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Nature
|August 27, 2015
概括
类切换重组 (CSR) 是为生产性删除定向而编程的. 这项研究揭示了一种前所未有的机制,涉及免疫球蛋白重链基因组织和激活诱导的cytidine deaminase启动的DNA双链断裂.
科学领域:
- 免疫学
- 分子生物学
- 遗传学
背景情况:
- B细胞的发育涉及RAG内核酶切割免疫球蛋白重链 (IgH) 基因段以组装V(D) J外.
- 在成熟的B细胞中,类切换重组 (CSR) 将Cμ常数区域外子替换为下游常数区域外子 (CHs).
- 通过激活诱导的cytidine deaminase (AID) 启动CSR,并且需要将DNA双链断裂 (DSB) 连接到删除方向.
研究的目的:
- 确定特定方向的连接是否是CSR的编程特征,类似于V(D) J重组.
- 调查企业社会责任实现生产性删除导向的机制.
- 确定执行企业社会责任的因素.
主要方法:
- 将高通量全基因组转位测序调整为敏感的DSB末端结合试验.
- 在小鼠B细胞中对内源性AID启动的S区域DSB进行测试.
主要成果:
- 企业社会责任是以生产性删除为导向的.
- 这种前所未有的机制涉及 cis IgH 组织特征和 AID 启动的 S 区域 DSB 促进了这一方向.
- 这种机制的执行涉及到依赖于ATM的DSB响应因子和53BP1.
结论:
- 企业社会责任是一个被编程的机制特征,而不是随机的.
- 这项研究阐明了一种实现生产性企业社会责任的新机制.
- 了解这些机制可以了解B细胞抗体类别的多样化和DNA修复途径.
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