Ataxia Telangiectasia: An Inherited Human Disease Involving Radiosensitivity, Malignancy and Defective DNA Repair
Ataxia Telangiectasia: An Inherited Human Disease Involving Radiosensitivity, Malignancy and Defective DNA Repair
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毛细血管扩张共济失调：一种涉及放射敏感性、恶性肿瘤和 DNA 修复缺陷的人类遗传性疾病
DOI：
10.1007/978-1-4613-4160-4_22
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发表时间：
1977
期刊：
影响因子：
--
通讯作者：
A. K. Anderson
中科院分区：
文献类型：
--
作者：
M. Paterson;B. P. Smith;P. A. Knight;A. K. Anderson
共济失调毛细血管扩张症（AT）是一种遗传性多系统疾病，其独特的特征是对电离辐射极度敏感，在临床和细胞培养中都观察到。因此，我们测量了来自不相关AT供体的10个二倍体成纤维细胞株在缺氧60Co γ辐照后的DNA修复能力。与两个对照菌株相比，10个突变株中有6个明显缺乏γ-诱导的修复复制。进一步确定了两个缺陷菌株。虽然能够正常地重新连接单链断裂，但在碱基缺陷的切除修复的初始切口步骤中，两者都受到损伤，作为对黄体微球菌内切酶活性敏感的γ修饰位点进行检测。细胞融合研究将三个修复缺陷菌株分配到两个互补组；这一结果，再加上10个AT菌株中有4个具有正常的修复复制能力，表明该疾病存在遗传异质性。AT菌株在其他方面表现正常，包括它们修复紫外线损伤的能力。除了为这种复杂的疾病提供分子视角外，我们的研究结果还将AT描述为紫外线敏感性皮肤病色素性干皮病的γ射线类似物。此外，由于AT患者易患癌症，有缺陷的DNA修复与肿瘤转化有关。最后，鉴于(i)胚胎分化受损最好地解释了AT的临床特征，（ii） DNA修复缺陷与病因学相关，我们得出结论，DNA损伤可导致先天性畸形；因此，酶促DNA修复过程在新生儿正常发育中起着至关重要的作用。
A unique feature of ataxia telangiectasia (AT), a hereditary multisystem disease, is extreme sensitivity to ionizing radiation, observed both clinically and in cell culture. Hence, we have measured the DNA repair capabilities of ten diploid fibroblast strains derived from unrelated AT donors, following anoxic 60Co γ-irradiation. Compared to two control strains, six of the ten mutant strains are markedly deficient in γ-induced repair replication. Two defective strains were defined further. While capable of rejoining single-strand breaks normally, both are impaired in the initial incision step in excision repair of base defects, assayed as γ-modified sites sensitive to a Micrococcus luteus endonuclease activity. Cell fusion studies assign three repair-deficient strains to two complementation groups; this result, coupled with a normal repair-replication ability in four of the ten AT strains, indicates genetic heterogeneity in the disease. AT strains appear otherwise normal, including their ability to repair UV damage. Aside from providing molecular insight into this complex disorder, our findings characterize AT as a γ-ray analogue of the UV-sensitive skin disease, xeroderma pigmentosum. Moreover, since AT patients are cancer-prone, faulty DNA repair is implicated in neoplastic transformation. Finally, given that (i) impaired embryonic differentiation best explains the clinical features of AT and (ii) defective DNA repair is of etiological relevance, we are led to conclude that DNA damage can lead to congenital malformations; thus, enzymatic DNA repair processes play a vital role in normal neonatal development.