The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, New York, United States.
Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, United States.
DNA Repair (Amst). 2018 Dec;72:10-17. doi: 10.1016/j.dnarep.2018.10.001. Epub 2018 Oct 11.
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 (Atm) in mice leads to embryonic lethality, raising the question of whether conditional expression of Atm in the murine nervous system would lead to a more pronounced neurological phenotype than Atm loss. We generated two mouse strains in which Atm 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 Atm 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 Atm 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.
基因组不稳定性综合征，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，导致该基因产物 ATM 蛋白激酶完全缺失或失活。ATM 是细胞对 DNA 双链断裂（DSB）反应的主要启动子-一个广泛的信号网络，其中许多成分是 ATM 的靶标。A-T 的主要临床特征是小脑萎缩，表现为浦肯野细胞和颗粒细胞的持续丧失。在 Atm 敲除（Atm-KO）小鼠中，完全缺失 Atm 导致非常轻微的神经表型，这表明 Atm 缺失不足以显著破坏该生物体的小脑结构和功能。在小鼠中表达无活性（“激酶失活”）的 Atm（Atm）导致胚胎致死，这引发了一个问题，即在小鼠神经系统中条件性表达 Atm 是否会导致比 Atm 缺失更明显的神经表型。我们生成了两种条件性表达 Atm 作为唯一 Atm 物种的小鼠品系：一种在中枢神经系统中，一种专门在浦肯野细胞中。我们将分析重点放在浦肯野细胞上，DSB 读数的动力学表明，与 Atm 缺失相比，DSB 修复在 Atm 存在下延迟更长时间。然而，两种品系都表现出正常的寿命，并且没有明显的小脑组织学异常或显著的神经表型。我们得出结论，与 Atm 缺失相比， Atm 的存在确实对 DSB 修复更有害，但小鼠中枢神经系统可以合理地耐受这种 DSB 修复损伤的程度。需要对基因组稳定性施加更大的压力，以获得能够重现严重 A-T 神经表型的小鼠模型。
