在加入DNA断裂时,ATM损伤反应和XLF修复因子在功能上是多余的
Shan Zha1, Chunguang Guo, Cristian Boboila
1Howard Hughes Medical Institute, The Children's Hospital, the Immune Disease Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|December 17, 2010
概括
涉及ATM和XLF的冗余DNA修复途径对于淋巴细胞发育至关重要. 这些因素的综合缺陷在V(D) J重组过程中损害了DNA末端连接,突出了它们在防止基因组不稳定性方面的重要作用.
科学领域:
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
背景情况:
- 经典非同源DNA末端结合 (NHEJ) 是修复哺乳动物DNA双链断裂 (DSB) 的主要途径.
- 像XRCC4这样的NHEJ因子的缺陷严重影响淋巴细胞发育,这是由于该途径在V(D) J重组中的作用.
- 虽然XLF (NHEJ1) 和ATM都涉及到NHEJ,但它们的确切作用,特别是考虑到功能冗余,仍然不完全理解.
研究的目的:
- 调查XLF,ATM和H2AX在DNA末端处理和V(D) J重组期间的连接中的功能作用.
- 阐明这些因素的综合缺陷对淋巴细胞发育和DNA修复的影响.
- 确定在经典的NHEJ中XLF和ATM之间的功能冗余背后的机制.
主要方法:
- 分析了ATM和XLF联合缺乏的小鼠的淋巴细胞发育情况.
- 在这些缺陷小鼠中评估V(D) J重组和IgH类切换重组.
- 研究ATM激酶活性和染色质相关基质的作用.
- 在XLF缺乏的亲B细胞系中,有条件的H2AX无活化.
主要成果:
- 结合ATM和XLF的缺乏严重阻碍了小鼠淋巴细胞的发育,原因是V(D) J重组DSB的处理和连接受损.
- 结合的XLF和ATM缺陷在IgH类切换重组过程中严重损害了经典的NHEJ,但不是替代的末端连接.
- 在经典的NHEJ中,ATM激酶活性与XLF调节冗余功能,特别是在染色素相关基质中.
- 在XLF缺乏细胞中的H2AX无活化导致V(D) J重组缺陷和未连接的DNA末端的降解.
结论:
- XLF,ATM和H2AX在V(D) J重组过程中在DNA末端连接中具有基本的,但隐蔽的作用,具有显著的功能冗余.
- 联合ATM和XLF缺陷突出了它们在淋巴细胞发育和DNA修复中的关键,多余的作用.
- 在经典的NHEJ中,ATM激酶活性和染色质背景对于ATM和XLF的冗余功能至关重要.
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