Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
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DOI：
10.1016/j.dnarep.2018.10.001
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发表时间：
2018-12
期刊：
影响因子：
3.8
通讯作者：
Shiloh Y
中科院分区：
文献类型：
--
作者：
Tal E;Alfo M;Zha S;Barzilai A;De Zeeuw CI;Ziv Y;Shiloh Y
基因组不稳定综合征，共济失调-毛细血管扩张症（A-T）是由ATM基因的无效突变引起的，这导致基因产物ATM蛋白激酶的完全丢失或失活。ATM是细胞对DNA双链断裂（DSB）反应的主要动员者，DSB是一个广泛的信号网络，其中许多组分是ATM靶点。A-T的主要临床特征是小脑萎缩，其特征在于浦肯野细胞和颗粒细胞的持续丧失。在Atm基因敲除（Atm-KO）小鼠中，Atm的完全丧失导致非常轻微的神经学表型，表明Atm丧失不足以显著废除该生物体中的小脑结构和功能。在小鼠中表达失活（“激酶死亡”）Atm（AtmKD）导致胚胎死亡，提出了AtmKD在鼠神经系统中的条件性表达是否会导致比Atm丢失更明显的神经学表型的问题。我们产生了两种小鼠品系，其中AtmKD有条件地表达为唯一的Atm物种：一种在CNS中，一种特异性地在浦肯野细胞中。将我们的分析集中在浦肯野细胞上，DSB读数的动力学表明，与Atm损失相比，在AtmKD存在下DSB修复延迟更长。然而，这两种菌株表现出正常的寿命，并显示没有明显的小脑组织学异常或显着的神经表型。我们的结论是，AtmKD的存在确实是更有害的DSB修复比Atm的损失，但小鼠中枢神经系统可以合理地容忍这种DSB修复损伤的程度。需要对基因组稳定性施加更大的压力，以获得重现严重A-T神经学表型的小鼠模型。
The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene’s product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) – a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebellar atrophy, characterized by relentless loss of Purkinje and granule cells. In Atm-knockout (Atm-KO) mice, complete loss of Atm leads to a very mild neurological phenotype, suggesting that Atm loss is not sufficient to markedly abrogate cerebellar structure and function in this organism. Expression of inactive (“kinase-dead”) Atm (AtmKD) in mice leads to embryonic lethality, raising the question of whether conditional expression of AtmKD in the murine nervous system would lead to a more pronounced neurological phenotype than Atm loss. We generated two mouse strains in which AtmKD was conditionally expressed as the sole Atm species: one in the CNS and one specifically in Purkinje cells. Focusing our analysis on Purkinje cells, the dynamics of DSB readouts indicated that DSB repair was delayed longer in the presence of AtmKD compared to Atm loss. However, both strains exhibited normal life span and displayed no gross cerebellar histological abnormalities or significant neurological phenotype. We conclude that the presence of AtmKD is indeed more harmful to DSB repair than Atm loss, but the murine central nervous system can reasonably tolerate the extent of this DSB repair impairment. Greater pressure needs to be exerted on genome stability to obtain a mouse model that recapitulates the severe A-T neurological phenotype.
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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：
10.1083/jcb.201204035
发表时间：
2012-08-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Daniel JA;Pellegrini M;Lee BS;Guo Z;Filsuf D;Belkina NV;You Z;Paull TT;Sleckman BP;Feigenbaum L;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
3.3
作者：
Chiesa, N;Barlow, C;Tempia, F
通讯作者：
Tempia, F
影响因子：
16.6
作者：
Croteau DL;Popuri V;Opresko PL;Bohr VA
通讯作者：
Bohr VA
影响因子：
64.5
作者：
Barlow, C;Hirotsune, S;WynshawBoris, A
通讯作者：
WynshawBoris, A