Telomere shortening

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

Herbert B. S., Pitts A. E., Baker S. I., Hamilton S. E., Wright W. E., Shay J.W., Corey D.R. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA 1999 96 14276-14281. 

NAASANI I, SEIMIYA H and TSURUO T (1998) Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins , Biochem Biophys Res Commun, 249 (2), 391-6. 

Riou JF et al. (2002) Cell senescence and telomere shortening induced by a new series of speciflc G-quadruplex DNA ligands. Proc Natl Acad Sci USA 99(5) 2672-2677... 

In summary, it will need to be demonstrated whether accelerated telomere shortening indeed represent the chronic phase clock reflecting both increased replicative aging of Ph-r HSC due to increased cell cycle activity as well as... 

Beier F, Balabanov S, Buckley T et al. Accelerated telomere shortening in glycosylphos-phatidylinositol (GPl) negative compared with GPl positive granuloc34es from patients with... 

Mathioudakis G, Storb R, McSweeney PA et al. Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients. Blood 2000 96 3991-3994. 

Rufer N, Brummendorf TH, Chapuis B et al. Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 2001 97 575-577. 

Brummendorf TH, Rufer N, Baerlocher GM, Roosnek E, Lansdorp PM. Limited telomere shortening in hematopoietic stem cells after transplantation. Ann.N.Y.Acad.Sci. 2001 938 1-7. 

Drummond M, Lennard A, Brummendorf T, Holyoake T. Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia. Leuk.Lymphoma 2004 45 1775-1781. 

Zhou JM, et al. (2006) Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 25(4) 503—511... 

The ends of chromosomes are protected from fusion, degradation or rearrangements by a repetitive DNA sequence known as the telomere [230]. In humans, telomeres comprise 500 to >2000 tandem repeats of the 6 bp sequence TTAGGG. Such a G-rich strand provides an attractive target for cisplatin. A recent study of cisplatin-treated HeLa cells suggested that a low dose of the drug causes telomere shortening due to incomplete replication... 

Hammerhead ribozymes that cleave the hTR RNA template have been shown to inhibit telomerase activity in human (66) and endometrial carcinomas (67,68) and in human melanoma cell extracts (69). Also, telomerase activity was down-regulated in vitro in endometrial carcinoma and human melanoma cells (68,69) however, no telomere shortening was observed in the human melanoma cells (69), and this approach to inhibition of telomerase activity has not been further investigated. 

Telomerase activity can also be inhibited by the direct binding of small non-nucleosidic synthetic compounds to the hTERT reverse transcriptase component of telomerase. Schnapp and coworkers have recently reported the first mixed-type noncompetitive (70) catalytic telomerase inhibitor, (2-((E)-3-naphtalen-2-yl-but-2-enoylamino)-benzoic acid) (BIBR1532), which causes telomere shortening and senescence characteristics in various types of cancer cells in vitro and in vivo in mouse xenograft models at nanomolar concentrations (71). 

As described before, an altered telomere state may be a more important consequence than critical telomere shortening (33). Thus, disruption of telesomes by either depletion of proteins involved in telomere binding (e.g., telomerase) or sequestration of telomere ends by stabilization of G-quadruplex structures, or both, may lead to chromosome end-to-end fusion in piesenescence cells. In fact, TMPyP4 and the fluoroquinophenoxazines have both been demonstrated to produce anaphase bridges, a hallmark of chromosome end fusions, in relatively short periods of time (78). 

The 9-anilino proflavine derivative was designed to optimize the interaction with the intramolecular G-quadruplex from human telomere and minimize that with duplex DNA. These compounds have 60 to 100 nM potency in a modified TRAP assay and corresponding low cytotoxicity (93). The triazines have been demonstrated to produce telomere shortening, which is associated with delayed growth arrest and cell senescence (80). The fluoroquinophenoxazines are redesigned topoisomerase II poisons that now interact more specifically with G-quadruplex structures, and this activity is correlated with production of anaphase bridges (78), a property also shared by the cationic porphyrin TMPyP4 (96) and... 

Makarov VL, Hirose Y, Langmore JP. 1997. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88 657-66... 

Harley CB, Futcher AB, Greider CW. 1990. Telomeres shorten during ageing of human fibroblasts. Nature 345 458-60... 

Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, et al. 1992. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11 1921 -29... 

Mehle C, Ljungberg B, Roos G. 1994. Telomere shortening in renal cell carcinoma. Cancer Res. 54 236—41... 

Rolyan H, Scheffold A, Heinrich A, Begus-Nahrmann Y, Langkopf BH, Holter SM et al (2011) Telomere shortening reduces Alzheimer s disease amyloid pathology in mice. Brain 134 2044-2056... 

S. E. Ball, F. M. Gibson, S. Rizzo, et al. Progressive telomere shortening in aplastic anemia. Blood 91,3582 (1998). 

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