Six Protein Core Complex Mediates Telomere End Protection

This telomeric t-loop is bound and stabilized by a number of telomere-specific binding proteins that form a six-protein complex, termed telosome (Liu et al. 2004) or shelterin (de Lange 2005). It is postulated that this highly regulated telomere structure serves three essential functions: (1) protecting natural chromosomal DNA ends from being inappropriately recognized as double-stranded breaks (DSBs) and therefore initiating an inappropriate DNA damage response (DDR), (2) protecting chromosomal ends from inappropriate enzymatic degradation, and (3) preventing chromosomal end-to-end fusion. Three sequence-specific DNA binding proteins are recruited to chromosomal ends: the duplex telomere-binding proteins TRF1 and TRF2 and the single-stranded TTAGGG repeat binding protein POT1 (Protection Of Telomeres 1). These proteins are interconnected by three additional proteins: TIN2, TPP1, and RAP1. TPP1 heterodimerizes with POT1 to augment its association with telomeres (Wang et al. 2007, Xin et al. 2007).

Mounting evidence suggests that POT1 is critical for telomere maintenance. It is highly conserved among eukaryotes and is the only protein in the complex that recognizes telomeric single-stranded DNA. All POT proteins examined to date contain two highly conserved oligonucleotide/oligosaccharide-binding folds (OB folds) that bind to the 3' terminus of the single-stranded G-rich telomeric overhang (Baumann and Cech 2001, Loayza and de Lange 2003, Wu et al. 2006). In accord with its end protective function, deletion of POT1 in a large variety of organisms results in chromosomal end-to-end fusions and activation of a DNA damage response. In addition, POT1 is also required to protect telomeres from participating in aberrant homologous recombination (HR) at telomeres (Wu et al. 2006). Since t-loops resemble Holliday junctions, substrates that readily undergo HR, POT1 functions to prevent telomeres from engaging in inappropriate recombination reactions. Inappropriate HR at telomeres could result in rapid telomere shortening and engagement of a p53-dependent senescence response (see below).

The POT1-TPP1 complex appears to play a major role in telomere length regulation. The POT1-TPP1 complex functions to both positively and negatively control telomere length. As a positive length regulator, the POT1-TPP1 complex binds telomerase to increase its activity and processitivity on telomeres (Wang et al. 2007, Xin et al. 2007). As a negative length regulator, POT1 inhibits telomerase activity by limiting its access to the terminal G residue of telomeres (Kelleher et al. 2005, Lei et al. 2005). Therefore, the POT1-TPP1 complex might modulate telomere length by recruiting telomerase to dysfunctional telomeric ends to promote regulated telomere extension.

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