Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression.
Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar degeneration, immunodeficiencies, genomic instability and gonadal atrophy. A-T patients are hypersensitive to ionizing radiation and have an elevated cancer risk. Cells derived from A-T patients require higher levels of serum factors, exhibit cytoskeletal defects and undergo premature senescence in culture. We show here that expression of the catalytic subunit of telomerase (hTERT) in primary A-T patient fibroblasts can rescue the premature senescence phenotype. Ectopic expression of hTERT does not rescue the radiosensitivity or the telomere fusions in A-T fibroblasts. The hTERT+AT cells also retain the characteristic defects in cell-cycle checkpoints, and show increased chromosome damage before and after ionizing radiation. Although A-T patients have an increased susceptibility to cancer, the expression of hTERT in A-T fibroblasts does not stimulate malignant transformation. These immortalized A-T cells provide a more stable cell system to investigate the molecular mechanisms underlying the cellular phenotypes of Ataxia-telangiectasia.
Wood
L D
LD
Department of Biology, University of California San Diego, La Jolla, California, CA 92093-0322, USA.
Halvorsen
T L
TL
Dhar
S
S
Baur
J A
JA
Pandita
R K
RK
Wright
W E
WE
Hande
M P
MP
Calaf
G
G
Hei
T K
TK
Levine
F
F
Shay
J W
JW
Wang
J J
JJ
Pandita
T K
TK
D000818:Animals; D001260:Ataxia Telangiectasia / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015197:Carcinogenicity Tests; D002453:Cell Cycle / Q000528:radiation effects; D002461:Cell Line, Transformed; D016922:Cellular Senescence; D002877:Chromosomes, Human / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects* / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012313:RNA; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012016:Reference Values; D012190:Retroviridae / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase