Telomeres are ribonucleoprotein heterochromatic structures at the ends of eukaryotic chromosomes that consist of tandem TTAGGG repeats bound by an array of associated proteins

Telomeres are ribonucleoprotein heterochromatic structures at the ends of eukaryotic chromosomes that consist of tandem TTAGGG repeats bound by an array of associated proteins (Chan and Blackburn, 2002; de Lange, 2002; Garcia-Cao et al., 2004). In addition, telomeres contain long non-coding AAUCCC-containing telomeric RNAs (TelRNAs or TERRAs), which are stably associated with the telomeric chromatin (Azzalin et al., 2007; Schoeftner and Blasco, 2008). Telomeric chromatin protects the 3 -single-stranded overhang (G-strand overhang) at the chromosome ends from degradation and prevents telomeres from being recognized as double-strand breaks (DSBs), probably through the formation of a looped structure (T-loop) (Griffith et al., 1999; de Lange, 2002; de Lange, 2004). Shortening of telomeres below a threshold length and/or altered functioning of the telomere-binding proteins result in a loss of telomere protection that leads to chromosomal endto-end fusions and cell cycle arrest and/or apoptosis, which in turn are proposed to impinge on the pathogenesis of cancer and aging (van Steensel et al., 1998; de Lange, 2005). Telomere length is regulated by the activity of a cellular reverse transcriptase known as telomerase (telomerase reverse transcriptase, TERT), which generates de novo telomeric repeats using an associated RNA molecule (telomerase RNA component, TERC) as a template (Chan and Blackburn, 2002). Telomere repeats are bound by a six-protein complex known as shelterin, which includes the POT1-TTP1 heterodimer and the telomere-binding proteins TRF1 and TRF2, as well as their interacting factors RAP1 and TIN2 (reviewed by de Lange, 2005; Liu et al., 2004; Ye et al., 2004; Smith et al., 1998). TRF2, together with other shelterin components, plays a crucial role in the regulation of telomere length and in telomere protection (de Lange, 2002; Muñoz et al., 2005). Deletion of TRF2 (also known as Terf2) in mice causes both embryonic lethality and a massive induction of end-to-end chromosome fusions in the absence of detectable telomere shortening (Celli and de Lange, 2005). However, the dramatic effect of TRF2 deletion on chromosomal integrity has little effect on the regeneration ability of some adult tissues, such as the liver (Celli and de Lange, 2005; Lazzerini Denchi et al., 2006), suggesting that TRF2 is not required to maintain the regenerative capacity of some adult stem cell compartments. Interestingly, mice with a 2–3-fold increase in telomere-bound TRF2 at the stem cell compartment of different epithelia [K5TRF2 mice; PM mouse line described in Muñoz et al. (Muñoz et al., 2005)] show severe telomere shortening and increased chromosomal instability in the presence of normal telomerase activity. K5TRF2 mice also show premature skin degenerative pathologies (hyperpigmentation, skin dryness, alopecia) and an increase in skin cancer; the latter is accelerated further in the absence of telomerase (Muñoz et al., 2005; Blanco et al., 2007). Interestingly, these K5TRF2 phenotypes are not rescued by telomerase overexpression, indicating that the short telomeres produced by TRF2 overexpression are not susceptible to elongation by telomerase; this is in agreement with loss of the G-strand overhang in these mice (Muñoz et al., 2005). Instead, the short telomeres in K5TRF2 transgenic mice are rescued by deletion of XPF (ERCC4), a component of the XPF-ERCC1 heterodimer, a TRF2-interacting nuclease involved in the repair of ultraviolet light (UV)-induced DNA damage through the nucleotide excision repair (NER) pathway (de Laat et al., 1999; Hoeijmakers, 2001; Zhu et al., 2003; Tian et al., 2004; Muñoz et al., 2005; Lazzerini Denchi et al., 2006), indicating that TRF2 overexpression shortens telomeres RESEARCH ARTICLE