Chromosome end associations, telomeres and telomerase activity in ataxia telangiectasia cells.
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.
Pandita
T K
TK
Center for Radiological Research, Columbia University, New York, NY 10032, USA.
Pathak
S
S
Geard
C R
CR
D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000235:genetics*; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D004247:DNA; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism*; D006801:Humans; D007621:Karyotyping; D016615:Telomere
D004247:DNA; D004253:DNA Nucleotidylexotransferase