Pandita T K
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
Radiat Res. 2001 Nov;156(5 Pt 2):642-7. doi: 10.1667/0033-7587(2001)156[0642:troait]2.0.co;2.
Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with a wide variety of phenotypic manifestations. AT patients are cancer prone and hypersensitive to ionizing radiation. Cells derived from AT patients require higher levels of serum factors, exhibit cytoskeletal defects, and undergo premature senescence in culture. The gene responsible for AT is ATM (ataxia-telangiectasia mutated), and its product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. The ATM gene product influences chromosome end associations, telomere length, and telomere clustering. The defective telomere metabolism in AT cells could be due to altered interactions between the telomeres and the nuclear matrix. These interactions were studied in nuclear matrix halos before and after irradiation. Altered telomere-nuclear matrix interactions were observed in cells derived from individuals with AT. AT cells also had different nucleosomal periodicity in their telomeres from normal cells. Both telomere-nuclear matrix interactions and nucleosomal periodicity were altered by treatment of primary AT fibroblasts with ionizing radiation. This effect was not observed in cells derived from normal individuals. A link was also found between altered telomere-nuclear matrix interactions, aberrant telomere clustering, and gonadal atrophy. The telomere defect was not corrected by the ectopic expression of the catalytic subunit of telomerase (TERT). Since alteration of the yeast telomere chromatin structure is known to influence gene expression, we compared expressed sequence tags (ESTs) of Atm-null mouse cells and normal mouse cells. Several ESTs were found to be aberrantly expressed in Atm-null mouse cells. This paper summarizes our recent publications and presents some new data on the influence of ATM on telomere metabolism.
共济失调毛细血管扩张症（AT）是一种罕见的人类常染色体隐性疾病，具有多种表型表现。AT患者易患癌症，对电离辐射高度敏感。来自AT患者的细胞需要更高水平的血清因子，表现出细胞骨架缺陷，并在培养中过早衰老。导致AT的基因是ATM（共济失调毛细血管扩张症突变基因），其产物与有丝分裂信号转导、染色体凝聚、减数分裂重组和细胞周期控制有关。由于人类ATM基因与酵母的TEL1和rad3基因具有同源性，有人提出ATM突变可能导致端粒维持缺陷。ATM基因产物影响染色体末端关联、端粒长度和端粒聚集。AT细胞中端粒代谢缺陷可能是由于端粒与核基质之间的相互作用改变所致。在辐射前后的核基质晕中研究了这些相互作用。在来自AT个体的细胞中观察到端粒与核基质相互作用的改变。AT细胞的端粒核小体周期性也与正常细胞不同。用电离辐射处理原代AT成纤维细胞会改变端粒与核基质的相互作用以及核小体周期性。在来自正常个体的细胞中未观察到这种效应。还发现端粒与核基质相互作用改变、端粒异常聚集和性腺萎缩之间存在联系。端粒酶催化亚基（TERT）的异位表达未纠正端粒缺陷。由于已知酵母端粒染色质结构的改变会影响基因表达，我们比较了Atm基因缺失小鼠细胞和正常小鼠细胞的表达序列标签（EST）。发现几个EST在Atm基因缺失小鼠细胞中异常表达。本文总结了我们最近的出版物，并提供了一些关于ATM对端粒代谢影响的新数据。
