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Pregled bibliografske jedinice broj: 196213

Abrupt telomere shortening in cell aging and cancer


Rubelj, Ivica
Abrupt telomere shortening in cell aging and cancer // Telomeres and telomerase
Cold Spring Harbor, SAD, 2005. (poster, nije recenziran, neobjavljeni rad, znanstveni)


CROSBI ID: 196213 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Abrupt telomere shortening in cell aging and cancer

Autori
Rubelj, Ivica

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
Telomeres and telomerase

Mjesto i datum
Cold Spring Harbor, SAD, 4-8.05. 2005

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
Telomeres; Telomerase; Abrupt telomere Shortening

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija



POVEZANOST RADA


Projekti:
0098077

Ustanove:
Institut "Ruđer Bošković", Zagreb

Profili:

Avatar Url Ivica Rubelj (autor)

Citiraj ovu publikaciju

Rubelj, Ivica
Abrupt telomere shortening in cell aging and cancer // Telomeres and telomerase
Cold Spring Harbor, SAD, 2005. (poster, nije recenziran, neobjavljeni rad, znanstveni)
Rubelj, I. (2005) Abrupt telomere shortening in cell aging and cancer. U: Telomeres and telomerase.
@article{article, author = {Rubelj, I.}, year = {2005}, keywords = {Telomeres, Telomerase, Abrupt telomere Shortening}, title = {Abrupt telomere shortening in cell aging and cancer}, keyword = {Telomeres, Telomerase, Abrupt telomere Shortening}, publisherplace = {Cold Spring Harbor, SAD} }
@article{article, author = {Rubelj, I.}, year = {2005}, keywords = {Telomeres, Telomerase, Abrupt telomere Shortening}, title = {Abrupt telomere shortening in cell aging and cancer}, keyword = {Telomeres, Telomerase, Abrupt telomere Shortening}, publisherplace = {Cold Spring Harbor, SAD} }




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