ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks.
ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks.
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DOI：
10.1038/nature09604
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发表时间：
2011-01-13
期刊：
影响因子：
64.8
通讯作者：
Alt, Frederick W.
中科院分区：
文献类型：
--
作者：
Zha, Shan;Guo, Chunguang;Boboila, Cristian;Oksenych, Valentyn;Cheng, Hwei-Ling;Zhang, Yu;Wesemann, Duane R.;Yuen, Grace;Patel, Harin;Goff, Peter H.;Dubois, Richard L.;Alt, Frederick W.
经典非同源DNA末端连接(C-NHEJ)是哺乳动物DNA双链断裂(DSB)修复的主要途径。C-NHEJ因子的缺乏，如XRCC4，破坏了淋巴细胞的发育，这是因为C-NHEJ必须加入V(D)J重组DSB中间体。XRCC4样因子(XLF)在某些免疫缺陷的人类患者中发生突变，并与C-NHEJ有关。然而，XLF缺陷小鼠的淋巴细胞发育相对正常，其淋巴细胞支持正常的V(D)J重组。共济失调毛细血管扩张突变蛋白(“ATM”)通过磷酸化包括组蛋白H_2AX在内的底物来检测DSB并激活DSB反应。然而，ATM缺乏只会引起V(D)J重组和淋巴细胞发育缺陷，而H_2AX缺乏对这些过程没有明显影响。在这里，我们证明了XLF、ATM和H2AX在V(D)J重组过程中都在处理和连接末端中发挥着基础作用；但这些作用被意想不到的功能冗余所掩盖。因此，由于不能处理和连接染色体V(D)J重组DSB中间体，ATM/XLF缺乏症几乎阻碍了小鼠淋巴细胞的发育。在IGH类交换机重组过程中，XLF和ATM的组合缺陷也会严重损害C-NHEJ，但不会影响可选的末端连接。C-NHEJ中多余的ATM和XLF功能是通过ATM激酶活性介导的，而不是染色体外V(D)J重组所必需的，这表明染色质相关的ATM底物起到了作用。相应地，在XLF缺失的Pro-B系中，有条件的H_2AX失活导致V(D)J重组缺陷与未连接的V(D)J末端的显著降解有关，这表明H_2AX确实在这一过程中发挥了作用。
Classical non-homologous DNA end-joining (C-NHEJ) is a major mammalian DNA double strand break (DSB) repair pathway. Deficiencies for C-NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for C-NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF) is mutated in certain immunodeficient human patients and has been implicated in C-NHEJ. Yet, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The Ataxia Telangiectasia-Mutated protein (“ATM”) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM-deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX-deficiency does not measurably impact these processes. Here, we show that XLF, ATM, and H2AX all have fundamental roles in processing and joining ends during V(D)J recombination; but that these roles have been masked by unanticipated functional redundancies. Thus, combined ATM/XLF-deficiency nearly blocks mouse lymphocyte development due inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs C-NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in C-NHEJ are mediated via ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, suggesting a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX indeed has a role in this process.
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影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
影响因子：
16
作者：
Callen, Elsa;Jankovic, Mila;Wong, Nancy;Zha, Shan;Chen, Hua-Tang;Difilippantonio, Simone;Di Virgilio, Michela;Heidkamp, Gordon;Alt, Frederick W.;Nussenzweig, Andre;Nussenzweig, Michel
通讯作者：
Nussenzweig, Michel
DOI：
10.1084/jem.20091320
发表时间：
2009-11-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Yin B;Savic V;Juntilla MM;Bredemeyer AL;Yang-Iott KS;Helmink BA;Koretzky GA;Sleckman BP;Bassing CH
通讯作者：
Bassing CH
DOI：
10.1084/jem.20041162
发表时间：
2004-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Reina-San-Martin B;Chen HT;Nussenzweig A;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
7.7
作者：
Yano, Ken-ichi;Morotomi-Yano, Keiko;Chen, David J.
通讯作者：
Chen, David J.