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Hiroyuki Niida1, Takehisa Matsumoto2, Hideo Satoh1, Mieko Shiwa1, Yoshiki Tokutake2, Yasuhiro Furuichi2 & Yoichi Shinkai1, 3
Nature Genetics - June 1998, volume 19 no. 2 pp 203 - 206
The ribonucleoprotein enzyme telomerase synthesizes telomeric DNA onto chromosome ends1. Telomere length is maintained, by the presence of telomerase activity, in the vast majority of primary tumours and stem cells2, 3, suggesting that telomere maintenance is essential for cellular immortalization. Recently, the telomerase RNA component in human4 and mouse5 (TERC and Terc, respectively), a telomerase-associated protein TEP1/TLP1 (refs 6,7) and the human catalytic subunit protein TERT (Refs 8,9) have been identified. To examine the role of telomerase in telomere maintenance and cellular viability, we established Terc-deficient embryonic stem (ES) cells. It is known that telomerase activity is absent in cells from Terc-knockout mice10. Although the study showed that telomere shortening was observed in the Terc-deficient cells from first to six generation animals, whether telomerase-dependent telomere maintenance was essential for cellular viability remained to be elucidated. To address this issue, we examined Terc-deficient ES cells under long-term culture conditions. Accompanying the continual telomere shortening, the growth rate of Terc-deficient ES cells was gradually reduced after more than 300 divisions. An impaired growth rate was maintained to approximately 450 divisions, and then cell growth virtually stopped. These data clearly show that telomerase-dependent telomere maintenance is critical for the growth of mammalian cells.
Hélène LaBranche1, Sophie Dupuis1, Yaacov Ben-David2, Maria-Rosa Bani2, Raymund J. Wellinger1 & Benoit Chabot1
Nature Genetics - June 1998, volume 19 no. 2 pp 199 - 202
Telomeric DNA of mammalian chromosomes consists of several kilobase-pairs of tandemly repeated sequences with a terminal 3´ overhang in single-stranded form. Maintaining the integrity of these repeats is essential for cell survival; telomere attrition is associated with chromosome instability and cell senescence, whereas stabilization of telomere length correlates with the immortalization of somatic cells1. Telomere elongation is carried out by telomerase, an RNA-dependent DNA polymerase which adds single-stranded TAGGGT repeats to the 3´ ends of chromosomes1. While proteins that associate with single-stranded telomeric repeats can influence tract lengths in yeast2, 3, equivalent factors have not yet been identified in vertebrates. Here, it is shown that the heterogeneous nuclear ribonucleoprotein A1 participates in telomere biogenesis. A mouse cell line deficient in A1 expression harbours telomeres that are shorter than those of a related cell line expressing normal levels of A1. Restoring A1 expression in A1-deficient cells increases telomere length. Telomere elongation is also observed upon introduction of exogenous UP1, the amino-terminal fragment of A1. While both A1 and UP1 bind to vertebrate single-stranded telomeric repeats directly and with specificity in vitro, only UP1 can recover telomerase activity from a cell lysate. These findings establish A1/UP1 as the first single-stranded DNA binding protein involved in mammalian telomere biogenesis and suggest possible mechanisms by which UP1 may modulate telomere length.
Tony L. Parkes1, Andrew J. Elia2, Dale Dickinson1, Arthur J. Hilliker1, John P. Phillips1 & Gabrielle L. Boulianne2
Nature Genetics - June 1998, volume 19 no. 2 pp 171 - 174
Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination1-3. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref. 4), suggests that chronic and unrepaired oxidative damage occurring specifically in motor neurons could be a critical causative factor in ageing. To test this hypothesis, we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons. We show that overexpression of a single gene, SOD1, in a single cell type, the motorneuron, extends normal lifespan by up to 40% and rescues the lifespan of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggests that the lifespan extension observed in these flies is due to enhanced RO metabolism. These results show that SOD activity in motorneurons is an important factor in ageing and lifespan determination in Drosophila.
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