Telomeres appear to be a key to switch human cells between mortality and immortality. Telomere shortening eventually triggers the check point mechanisms leading to replicative senescence, while maintenance of telomeres, for instance by active telomerase, allows unrestricted growth. We have shown that a major reason for the shortening of telomeres (in addition to a minor contribution from the end-replication problem) is oxidative damage, combining for the first time the free radical theory of ageing with the telomere hypothesis of cellular senescence (von Zglinicki et al 1995, von Zglinicki et al 2000). In comparison to the rest of the genome, telomeres are somewhat deficient in single-strand break (base excision) repair (Petersen et al 1998), resulting in telomere-specific accumulation of damage in non-dividing cells, which in turn hinders complete replication of telomeres, leading to telomere shortening during DNA replication (Sitte et al 1998, von Zglinicki 2000). We demonstrated that free single-stranded G-rich telomeric DNA (free overhangs) are potent trigger for a p53-dependent, senescence-like cell cycle arrest (Saretzki et al 1999). In addition, we were interested in inhibition of telomerase in tumor cells (Mueller et al 1998) and in the role of protein turnover and lipofuscin accumulation during replicative senescence and postmitotic ageing (Sitte et al 2000a, b).
Cellular ageing and telomere maintenance: Accelerated telomere shortening due to increased oxidative stress results in premature ageing of normal cells, while senescence can be delayed if the telomere shortening rate is decreased by increasing the cell's antioxidative capacity. Telomerase activation occurs most probable at crisis, and can result in immortal growth.
Our ongoing projects include:
Examination of the role of cellular and individual antioxidative defence mechanisms for telomere maintenance and shortening, including the evaluation of intra-individual correlations between different cell types as well as the identification of stress response genes involved by array technology.
Investigation of the influence of certain telomere-binding proteins on the efficiency of telomeric single-strand break repair.
Investigation of the prognostic potential of telomere length with regards to age-related degenerative diseases in humans.
Inhibition of telomerase in breast tumor cells using a ribozyme to cleave hTERT mRNA, on its own and in combination with DNA-damaging chemotherapeutic treatments.