Pandita T K, Dhar S
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.
Radiat Res. 2000 Aug;154(2):133-9. doi: 10.1667/0033-7587(2000)154[0133:ioafoi]2.0.co;2.
The ATM (ataxia telangiectasia mutated) gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. 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. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia (AT), influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in AT cells is due to altered interactions between the telomeres and the nuclear matrix. These interactions were examined in nuclear matrix halos prior to and after irradiation. A difference was observed in the ratio of soluble and matrix-associated telomeric DNA between cells derived from AT and normal individuals. Treatment with ionizing radiation affected the ratio of soluble and matrix-associated telomeric DNA only in the AT cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, such interactions were examined in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix seen in AT cells. Fibroblasts from AT individuals transfected with a wild-type ATM gene had corrected telomere-nuclear matrix interactions. In experiments designed to determine whether there is a link between the altered telomere-nuclear matrix interactions and defective telomere movement and clustering, a significant difference was observed in the ratio of soluble compared to matrix-associated telomeric DNA sequences in meiocytes of Atm(-/-) and control mice. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix and that alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. This paper summarizes our recent publications on the influence of inactivation of ATM on the interaction of telomeres with nuclear matrix in somatic and germ cells.
共济失调毛细血管扩张症突变（ATM）基因产物与有丝分裂原信号转导、染色体凝聚、减数分裂重组及细胞周期调控有关。人类ATM蛋白与参与减数分裂重组和细胞周期进程的几种酵母及哺乳动物蛋白具有相似性。由于人类ATM基因与酵母的TEL1和rad3基因存在同源性，有人提出ATM突变可能导致端粒维持缺陷。最近，我们发现，在易患癌症的共济失调毛细血管扩张症（AT）中存在缺陷的ATM基因产物会影响染色体末端关联和端粒长度。解释这些结果的一个可能假说是，AT细胞中端粒代谢缺陷是由于端粒与核基质之间相互作用的改变。在照射前后的核基质晕中对这些相互作用进行了检测。在源自AT个体和正常个体的细胞之间，观察到可溶性和与基质相关的端粒DNA比例存在差异。电离辐射处理仅影响AT细胞中可溶性和与基质相关的端粒DNA比例。为了验证ATM基因产物参与端粒与核基质之间相互作用的假说，在表达ATM基因显性负效应或互补效应的人类细胞中检测了这种相互作用。表达含有亮氨酸拉链基序的ATM片段的RKO结肠直肠肿瘤细胞的表型模拟了AT细胞中端粒与核基质相互作用的改变。用野生型ATM基因转染的AT个体的成纤维细胞纠正了端粒 - 核基质相互作用。在旨在确定端粒 - 核基质相互作用改变与端粒运动和聚集缺陷之间是否存在联系的实验中，在Atm(-/-)小鼠和对照小鼠的减数分裂细胞中，观察到可溶性与与基质相关的端粒DNA序列比例存在显著差异。这些结果表明，ATM基因影响端粒与核基质之间的相互作用，端粒染色质的改变可能至少部分导致了ATM基因的多效性表型。本文总结了我们最近发表的关于ATM失活对体细胞和生殖细胞中端粒与核基质相互作用影响的研究成果。
