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Telomerase and cell senescence: modulation by telomerase of cellular responses to damage in normal human primary skin keratinocytes and fibroblasts

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Telomeres protect the ends of chromosomes, which contain the DNA that comprises the genetic information. Without telomeres and their special way of replicating, chromosome ends dwindle away and also are easily damaged. Loss of telomere function promotes cancer and may occur in human aging. Most enzymes – the catalysts that carry out life's chemical reactions – are made of protein. In contrast, the enzyme telomerase, which replenishes the DNA at telomeres and protects them, is a ribonucleoprotein complex consisting of core components – a protein reverse transcriptase and the telomerase RNA moiety – as well as additional protein factors that regulate the action of telomerase on telomeres.

A major known function of telomerase is to elongate telomeric DNA. This function is achieved by the enzyme copying a short template sequence within the inbuilt telomerase RNA, into telomeric DNA repeat sequences. The mechanism of telomerase has been analyzed and telomerase has been shown to be a dimeric enzyme. Functional dimerization of human telomerase requires a novel RNA–RNA interaction between two telomerase RNA molecules in the same enzyme complex. Telomeric repeats are added to the end of the chromosomal DNA by telomerase, elongating the chromosome and thus compensating for losses of terminal DNA that occur upon nuclease action and incomplete DNA replication of the ends of the chromosomal DNA.

However, telomerase is largely repressed in proliferating cultured human fibroblasts or after a few passages of culturing of primary human keratinocytes. The normal senescence of such fibroblasts and other human cell types in culture can be overcome by forced expression of telomerase in these cells. The lifespan of the cells is extended and they grow healthily, generally without evidence of impairment to DNA checkpoint pathways.

We analyzed the effects of forced expression of telomerase on the growth characteristics and sensitivity to ultraviolet (UV) irradiation of primary human cells in culture. Normal primary human foreskin epithelial keratinocytes and fibroblasts were stably infected with retroviral vector expressing various versions of hTERT (the reverse transcriptase protein component of telomerase), or the control empty retroviral vector pBABEpuro. Cells selected for the puromycin drug resistance marker were continuously passaged in puromycin-containing media, and their telomeres, cell growth and cell viability analyzed. The responses of such cells expressing telomerase to different challenges, including UV exposure were analyzed and found to differ from those of control cells.
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Document Type: Abstract

Affiliations: Department of Biochemistry and Biophysics, University of California, San Francisco, U.S.A.

Publication date: April 1, 2004

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