Nalazite se na CroRIS probnoj okolini. Ovdje evidentirani podaci neće biti pohranjeni u Informacijskom sustavu znanosti RH. Ako je ovo greška, CroRIS produkcijskoj okolini moguće je pristupi putem poveznice www.croris.hr
izvor podataka: crosbi !

Abrupt telomere shortening in cell aging and cancer (CROSBI ID 506745)

Neobjavljeno sudjelovanje sa skupa | neobjavljeni prilog sa skupa

Rubelj, Ivica Abrupt telomere shortening in cell aging and cancer // Telomeres and telomerase Cold Spring Harbor (NY), Sjedinjene Američke Države, 04.05.2005-08.05.2005

Podaci o odgovornosti

Rubelj, Ivica

engleski

Abrupt telomere shortening in cell aging and cancer

A strong stochastic component has been described for the appearance of senescent cells in cultures that have not completed their in vitro lifespan. The proliferative potential of individual clones shows a bimodal distribution. Additionally, two cells arising from a single mitotic event can exhibit large differences in their doubling capacities. We present a molecular model and a computer simulation of the model that explains the observed stochastic phenomena. The model is based on a combination of both, gradual telomere shortening (GTS) and abrupt telomere shortening (ATS) (1). GTS occurs as a consequence of the inability of DNA polymerase to replicate the very end of chromosomal DNA as well as exonuclease degradation of the 5' strand at telomere ends (2). GTS could be responsible for the gradual decline in proliferative potential of a cell culture, but does not explain the stochastic aspects of cellular aging. ATS is predicted to occur through strand invasion of the 3’ overhang into the telomeric/subtelomeric border region followed by formation of a t-loop structure which has later been found in normal and immortal human and mouse cells (3). ATS is mediated by Holiday structure formation which results in a deletion of distal telomeric repeats through circularisation. Our model explains the gradual increase of senescent cells in a culture by proposing that long telomeres have a stable conformation and a low probability of undergoing abrupt shortening but, as telomere shortening progresses the probability of conformation changes to an unstable form increases almost exponentially. Abrupt shortening of one or more telomeres in the cell causes cell cycle arrest within one cell division. Since it was published, all of the predictions of our model have been examined both structurally (3) and functionally (4) including the presence of ultrashort, single telomeres in senescent human cells (5), the identification of circular telomeric DNA in various mammalian cell lines (6), generation of t-loop-sized deletions at human telomeres by homologous recombination in ALT cells (4) and along with the observations of Hemann et al (7) and Smith & Whitney (8) strongly suggest catastrophic telomere deletion as the mechanism that induces the stochastic p21/pRB mediated permanent cell-cycle arrest observed in normal human cell cultures. This concept is further supported by our latest experiments in which we compared the telomere lengths of a subpopulation of senescent human skin fibroblasts, present in pre-senescent cultures, with those of young cells (9). Our results demonstrate that telomeres of early-senescing cells are the same length, and must shorten at the same rate, as cycling sister cells in the culture, this is the expected result if abrupt shortening of a single telomere triggers the onset of cell senescence.

Telomeres; Telomerase; Abrupt telomere Shortening

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

nije evidentirano

Podaci o prilogu

nije evidentirano

nije evidentirano

Podaci o skupu

Telomeres and telomerase

poster

04.05.2005-08.05.2005

Cold Spring Harbor (NY), Sjedinjene Američke Države

Povezanost rada

Biologija