RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'.
RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'.
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DOI：
10.1093/nar/gku295
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发表时间：
2014-06
影响因子：
14.9
通讯作者：
Roth DB
中科院分区：
文献类型：
--
作者：
Gigi V;Lewis S;Shestova O;Mijušković M;Deriano L;Meng W;Luning Prak ET;Roth DB
DNA双链断裂（DSBs）可以通过几种机制修复，包括经典的NHEJ （c-NHEJ）和定义不清、容易出错的替代NHEJ （a-NHEJ）过程。细胞如何在这些替代方案中选择加入生理性dsb仍然未知。在这里，我们发现RAG2的c端缺失允许a-NHEJ修复来自c- nhej富集和c- nhej缺陷小鼠的发育淋巴细胞中RAG2介导的dsb，这表明V(D)J重组酶影响体内修复途径的选择。V(D)J结的分析表明，与预期相反，仅靠连接特征并不能可靠地区分a-NHEJ和c-NHEJ。这些数据表明，a-NHEJ不一定具有诱变性，而且可能比以前认为的更为普遍。在c端RAG2截断的p53 - / -小鼠中发生的淋巴瘤的全基因组测序显示了a- nhej的证据，以及类似RAG识别位点的DNA序列的异常识别。
DNA double-stranded breaks (DSBs) can be repaired by several mechanisms, including classical NHEJ (c-NHEJ) and a poorly defined, error-prone process termed alternative NHEJ (a-NHEJ). How cells choose between these alternatives to join physiologic DSBs remains unknown. Here, we show that deletion of RAG2's C-terminus allows a-NHEJ to repair RAG-mediated DSBs in developing lymphocytes from both c-NHEJ-proficient and c-NHEJ-deficient mice, demonstrating that the V(D)J recombinase influences repair pathway choice in vivo. Analysis of V(D)J junctions revealed that, contrary to expectation, junctional characteristics alone do not reliably distinguish between a-NHEJ and c-NHEJ. These data suggest that a-NHEJ is not necessarily mutagenic, and may be more prevalent than previously appreciated. Whole genome sequencing of a lymphoma arising in a p53−/− mouse bearing a C-terminal RAG2 truncation reveals evidence of a-NHEJ and also of aberrant recognition of DNA sequences resembling RAG recognition sites.
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影响因子：
14.9
作者：
Curry JD;Schlissel MS
通讯作者：
Schlissel MS
DOI：
10.1073/pnas.0237043100
发表时间：
2003-02-04
影响因子：
11.1
作者：
Akamatsu, Y;Monroe, R;Oettinger, MA
通讯作者：
Oettinger, MA
影响因子：
14.9
作者：
CUOMO, CA;OETTINGER, MA
通讯作者：
OETTINGER, MA
影响因子：
14.9
作者：
Boubakour-Azzouz, Imenne;Bertrand, Pascale;Rougeon, Francois
通讯作者：
Rougeon, Francois
影响因子：
14.9
作者：
CLARK, JM
通讯作者：
CLARK, JM