Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways
Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways
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DOI：
10.1096/fj.11-185546
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发表时间：
2011-11-01
期刊：
影响因子：
4.8
通讯作者：
Wiesmueller, Lisa
中科院分区：
文献类型：
--
作者：
Keimling, Marlen;Volcic, Meta;Wiesmueller, Lisa
共济失调性毛细血管扩张症突变体（ATM）具有同源重组（HR）和非同源末端连接（NHEJ）等多种功能，导致以往关于其DNA双链断裂修复（DSBR）功能的研究存在争议。为了探索临床相关ATM突变的影响，我们表征了9个淋巴母细胞样细胞系（LCL）中突变的EGFP基因和ATM激酶信号传导之间的DSBR，所述LCL来源于患有共济失调毛细血管扩张症（AT）的患者，具有确定的LCL与3个没有ATM突变的对照LCL。我们的研究表明，AT细胞中的DSBR表型并不均匀，但似乎取决于突变，导致特定途径的活性增加32倍或降低3倍。与另外10个下游因子突变的LCL（BRCA 1、BRCA 2、Nitrifos、Rad 50和Chk 2）的比较显示，AT细胞中最截然相反的DSBR模式表型模仿NBN/RAD 50或BRCA 1突变。值得注意的是，重新表达野生型ATM逆转了这些缺陷2.3至3.5倍。我们的数据表明，ATM刺激修复蛋白，如NITARY，它执行HR，单链退火（SSA）和NHEJ。同时，ATM通过激活BRCA 1等监测因子，最大限度地减少易错修复（SSA和NHEJ）。由于个体缺陷的结果可能是完全相反的，因此区分ATM突变患者的修复模式也可能与治疗反应有关。Keimling，M.，Volcic，M.，Csernok，A.，Wieland，B.，呆子T维斯米勒湖功能表征将共济失调毛细血管扩张症突变（ATM）中的个体患者突变与特定DNA双链断裂修复信号通路的功能障碍联系起来。FASEB J.25，3849-3860（2011）。www.fasebj.org
Ataxia telangiectasia mutated (ATM) has multiple functions in homologous recombination (HR) and nonhomologous end joining (NHEJ), which lead to conflicting data regarding its DNA double-strand break-repair (DSBR) functions in previous studies. To explore the effect of clinically relevant ATM mutations, we characterized DSBR between mutated EGFP genes and ATM kinase signaling in 9 lymphoblastoid cell lines (LCLs) derived from patients with ataxia telangiectasia (AT) with defined vs. 3 control LCLs without ATM mutations. Our study revealed that the DSBR phenotype in AT cells is not uniform but appears to depend on the mutation, causing up to 32-fold increased or up to 3-fold decreased activities in particular pathways. Comparison with a further 10 LCLs mutated in downstream factors (BRCA1, BRCA2, Nibrin, Rad50, and Chk2) showed that the most diametrically opposed DSBR patterns in AT cells phenocopied NBN/RAD50 or BRCA1 mutations. Notably, reexpressing wild-type ATM reversed these defects by 2.3- to 3.5-fold. Our data suggest that ATM stimulates repair proteins such as Nibrin, which execute HR, single-strand annealing (SSA), and NHEJ. Concomitantly, ATM minimizes error-prone repair (SSA and NHEJ) through activation of surveillance factors such as BRCA1. Since the outcome of the individual defect can be diametrically opposed, distinguishing repair patterns in patients with ATM mutations may also be relevant regarding therapeutic responses.-Keimling, M., Volcic, M., Csernok, A., Wieland, B., Dork, T., Wiesmuller, L. Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways. FASEB J. 25, 3849-3860 (2011). www.fasebj.org