Pandita T K, Pathak S, Geard C R
Center for Radiological Research, Columbia University, New York, NY 10032, USA.
Cytogenet Cell Genet. 1995;71(1):86-93. doi: 10.1159/000134069.
Cells derived from individuals with ataxia telangiectasia (AT) show enhanced spontaneous levels of chromosomal abnormalities and are sensitive to ionizing radiations and radiomimetic drugs, as evidenced by decreased survival and increased chromosome aberration frequencies at mitosis when compared with normal cell lines. The higher base line frequencies of chromosome aberrations in part involve chromosome end-to-end associations as seen at metaphase. Since telomeres of tumor cells and aging tissues are often reduced in length, chromosome end associations may be due to loss of telomeric repeats. We studied the chromosome behavior and telomeres of two ataxia telangiectasia lymphoblastoid cell lines compared to two normal control cell lines. The ataxia telangiectasia cell lines showed higher frequencies of chromosome end associations both at metaphase and in interphase, determined in prematurely condensed chromosomes of G1 and G2 cells. They also showed higher frequencies of chromosomal breaks at metaphase and fewer telomeric signals determined using fluorescent in situ hybridization with a (TTAGGG)n probe. The frequency of telomeric repeats was variable in the ataxia telangiectasia cell lines (4.3 and 8.2 kb) compared to the normal cell lines (9.6 and 12 kb) and an inverse correlation between telomere length and chromosome end associations was observed. Both ataxia telangiectasia cell lines showed more robust telomerase activity than the normal cell lines, precluding defective enzymatic capacity as the basis for the chromosome end associations. It is possible that chromatin structure in the form of telomere-nuclear matrix interactions are variant in ataxia telangiectasia cells negatively influencing telomerase function and contributing to telomere associations.
共济失调毛细血管扩张症（AT）患者来源的细胞显示出更高的自发染色体异常水平，并且对电离辐射和拟辐射药物敏感，与正常细胞系相比，有丝分裂时细胞存活率降低以及染色体畸变频率增加就证明了这一点。染色体畸变的较高基线频率部分涉及中期可见的染色体端对端关联。由于肿瘤细胞和衰老组织的端粒长度常常缩短，染色体末端关联可能是由于端粒重复序列的丢失所致。我们研究了两个共济失调毛细血管扩张症淋巴母细胞系与两个正常对照细胞系的染色体行为和端粒。共济失调毛细血管扩张症细胞系在中期和间期均显示出更高的染色体末端关联频率，这是在G1和G2期细胞的早熟凝集染色体中测定的。它们在中期也显示出更高的染色体断裂频率，并且使用（TTAGGG）n探针进行荧光原位杂交测定的端粒信号更少。与正常细胞系（9.6和12 kb）相比，共济失调毛细血管扩张症细胞系中端粒重复序列的频率是可变的（4.3和8.2 kb），并且观察到端粒长度与染色体末端关联之间呈负相关。两个共济失调毛细血管扩张症细胞系均显示出比正常细胞系更强的端粒酶活性，排除了酶功能缺陷是染色体末端关联的基础。共济失调毛细血管扩张症细胞中端粒-核基质相互作用形式的染色质结构可能存在变异，对端粒酶功能产生负面影响并导致端粒关联。
