Research on the molecular pathology of genome instability disorders has advanced our understanding of the complex mechanisms that safeguard genome stability and cellular homeostasis at large. Once the culprit genes and their protein products are identified, an ongoing dialogue develops between the research lab and the clinic in an effort to link specific disease symptoms to the functions of the proteins that are missing in the patients. Ataxi A-T elangiectasia (A-T) is a prominent example of this process. A-T’s hallmarks are progressive cerebellar degeneration, immunodeficiency, chronic lung disease, cancer predisposition, endocrine abnormalities, segmental premature aging, chromosomal instability and radiation sensitivity. The disease is caused by absence of the powerful protein kinase, ATM, best known as the mobilizer of the broad signaling network induced by double-strand breaks (DSBs) in the DNA. In parallel, ATM also functions in the maintenance of the cellular redox balance, mitochondrial function and turnover and many other metabolic circuits. An ongoing discussion in the A-T field revolves around the question of which ATM function is the one whose absence is responsible for the most debilitating aspect of A-T – the cerebellar degeneration. This review suggests that it is the absence of a comprehensive role of ATM in responding to ongoing DNA damage induced mainly by endogenous agents. It is the ensuing deterioration and eventual loss of cerebellar Purkinje cells, which are very vulnerable to ATM absence due to a unique combination of physiological features, which kindles the cerebellar decay in A-T.

基因组不稳定性疾病的分子病理学研究提高了我们对维护基因组稳定性和总体细胞稳态的复杂机制的理解。一旦确定了罪魁祸首的基因及其蛋白质产物，研究实验室与诊所之间便会展开持续的对话，以期将特定的疾病症状与患者所缺少的蛋白质功能联系起来。共济失调AT血管扩张（AT）是该过程的一个突出例子。A-T的标志是进行性小脑变性，免疫缺陷，慢性肺病，癌症易感性，内分泌异常，节段性早衰，染色体不稳定和放射敏感性。该疾病是由于缺乏强大的蛋白激酶ATM引起的，最著名的是由DNA中的双链断裂（DSB）诱导的广泛信号网络的动员者。同时，ATM还可以维持细胞氧化还原平衡，线粒体功能和更新以及许多其他代谢循环。在AT领域正在进行的讨论围绕着一个问题，即ATM的功能是谁的缺失导致了AT的最衰弱方面-小脑变性。这项审查表明，在应对主要由内源性药物引起的持续性DNA损伤中，ATM缺乏全面的作用。正是随之而来的小脑浦肯野细胞的退化和最终的丧失，由于生理特征的独特组合，它们非常容易出现ATM缺失，从而点燃了AT的小脑衰弱。