In somatic cells where telomerase is not active, telomeric DNA shortens with each cell division (Harley et al. 1990, Hastie et al. 1990). This may be especially pronounced in cells undergoing replicative exhaustion due to oncogenic signaling-driven cell division. The shelterin complex, which protects telomeres from being recognized as double strand DNA breaks (reviewed by de Lange 2005), binds telomeric DNA through interaction of its subunits TREF1 (TRF1) and TREF2 (TRF2) with long TTAGGG repeat tracts (Smogorzewska et al. 2000). Telomere shortening due to replicative exhaustion results in a decreased number of TTAGGG repeats, which negatively impacts shelterin binding to telomeric DNA.