Lavin M F, Khanna K K
The Queensland Cancer Fund Research Unit, The Queensland Institute of Medical Research, Brisbane, Australia.
Int J Radiat Biol. 1999 Oct;75(10):1201-14. doi: 10.1080/095530099139359.
To provide an update on the product of the ATM gene mutated in the human genetic disorder ataxia-telangiectasia (A-T).
The product of the ATM gene mutated in the human genetic disorder A-T is a 350 kDa protein that plays a central role in the regulation of a number of cellular processes. It is a member of the phosphatidylinositol 3-kinase superfamily, but is more likely a protein kinase similar to another member of that family, i.e. DNA-dependent protein kinase (DNA-PK). A-T cells and fibroblasts derived from the atm -/- mouse are hypersensitive to ionizing radiation and defective in cell cycle checkpoint control. At present the nature of the lesion in damaged DNA recognized by ATM remains uncertain, but it is evident that a small number of residual strand breaks remain unrepaired in A-T cells, which may well account for the radiosensitivity. On the other hand, considerable progress has been achieved in delineating the role of ATM in cell cycle checkpoint control. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation. At the G1 /S interface ATM has been shown to play a central role in radiation-induced activation of the tumour suppressor gene product p53. ATM binds to p53 in a complex fashion and activates the molecule in response to breaks in DNA by phosphorylating it at serine 15 close to the N-terminus and by controlling other phosphorylation and dephosphorylation changes on the molecule. This in turn leads to the induction of p21/WAF1 and other p53 effector proteins before inhibition of cyclin-dependent kinase activity and G1 arrest. Emerging evidence supports a direct role for ATM at other cell cycle checkpoints. Other proteins interacting with ATM include c-Abl a protein tyrosine kinase, beta-adaptin an endosomal protein and p21 a downstream effector of p53. The significance of these interactions is currently being investigated. ATM also plays an important role in the regulation and surveillance of meiotic progression. The localization of ATM to both the nucleus and other subcellular organelles implicates this molecule in a myriad of cellular processes.
ATM is involved in DNA damage recognition and cell cycle control in response to ionizing radiation damage. There is evidence that ATM may also have a more general signalling role.
提供关于在人类遗传性疾病共济失调毛细血管扩张症（A-T）中发生突变的ATM基因产物的最新信息。
在人类遗传性疾病A-T中发生突变的ATM基因产物是一种350 kDa的蛋白质，它在许多细胞过程的调节中起核心作用。它是磷脂酰肌醇3激酶超家族的成员，但更可能是一种蛋白激酶，类似于该家族的另一个成员，即DNA依赖性蛋白激酶（DNA-PK）。来自atm-/-小鼠的A-T细胞和成纤维细胞对电离辐射高度敏感，并且在细胞周期检查点控制方面存在缺陷。目前，ATM识别的受损DNA损伤的性质仍不确定，但很明显，A-T细胞中仍有少量残留的链断裂未得到修复，这很可能是放射敏感性的原因。另一方面，在描绘ATM在细胞周期检查点控制中的作用方面已经取得了相当大的进展。照射后A-T细胞的所有细胞周期检查点都观察到缺陷。在G1/S界面，ATM已被证明在辐射诱导的肿瘤抑制基因产物p53的激活中起核心作用。ATM以复杂的方式与p53结合，并通过在靠近N端的丝氨酸15处磷酸化p53以及控制该分子上的其他磷酸化和去磷酸化变化来响应DNA断裂而激活该分子。这反过来又导致在抑制细胞周期蛋白依赖性激酶活性和G1期停滞之前诱导p21/WAF1和其他p53效应蛋白。新出现的证据支持ATM在其他细胞周期检查点的直接作用。与ATM相互作用的其他蛋白质包括蛋白酪氨酸激酶c-Abl、内体蛋白β-衔接蛋白和p53的下游效应物p21。目前正在研究这些相互作用的意义。ATM在减数分裂进程的调节和监测中也起重要作用。ATM定位于细胞核和其他亚细胞器，这表明该分子参与了无数的细胞过程。
ATM参与了对电离辐射损伤的DNA损伤识别和细胞周期控制。有证据表明ATM可能还具有更普遍的信号作用。
