Clinical aspects relevant to telomere maintenance and therapeutic opportunities

Telomeres are tandem repeated DNA sequence (TTAGGG)n that cap linear chromosomes to maintain stability (Blackburn 1991). Telomeres shorten with successive rounds of DNA replication during sequential cell division (Harley et al. 1990). Although tissues start off with equivalent telomeres, changes in telomere length occur in parallel but at different rates during the lifespan of each individual (Hastie et al. 1990, Kim et al. 2002, O‘Sullivan et al. 2006). Humans begin life with roughly 13,000 base pairs of telomere in their leukocytes. In young adulthood, approximately 33 base pairs of peripheral blood leukocyte telomere length are lost annually, and this annual loss intensifies to roughly 61 base pairs of telomere after 60 years of age (Epel et al. 2004). Telomere shortening mitigates the end-replication problem, where the incomplete replication of linear DNA could result in the loss of genetic material. In healthy cells, erosion of telomere length eventually leads to regulated cell senescence and apoptosis. Telomere length and the shortening that occurs over rounds of cell division have been identified as a marker of biological age, representing a “molecular clock.” Telomeres are 10-15 kilobases of gene-poor material, characterized by the 163binding of large protein complexes-telomere repeat binding factors (TRF1 and 2)-directly to telomeric repeats and then interact with other factors, which provides one level of telomere regulation (Blackburn 1991, 2001). This regulation broadly has a role in preventing telomere end-to-end fusions, by DNA repair mechanisms through direct interaction with TRF2 (Smogorzewska and de Lange 2004). Telomere repeat binding factors are a part of the shelterin complex, which also includes TRF1 interacting protein 2 (TIN2), protection of telomeres 1 (POT1), the POT1 and TIN2 interacting protein TPP1 and the transcriptional repressor/activator protein RAP1 (de Lange 2005a). Some of the shelterin components do not bind directly to telomere DNA, but interact and form complexes (heterodimerization) with TRF1 and TRF2. In a mouse model with the deletion of shelterin components, there were high levels of telomere dysfunction, DNA damage response and chromosomal instability (Deng et al. 2008).