Telomere Dysfunction and the DNA Damage Response

In the absence of a protective state at telomeres, chromosome ends become dysfunctional and may ultimately contribute to genomic instability. To avoid the disruption of telomere(definition) function, a host of telomere-binding and associated proteins are critically involved in maintaining structure and preventing subsequent activation of a DNA damage response. In addition to these factors, a multitude of DNA damage response proteins also normally localize to the telomere, without triggering a repair response or cell cycle arrest. Their involvement suggests that telomere maintenance and the damage response are highly interdependent for ensuring genomic integrity. In this regard, a paradigm emerges in which telomeres may actually act as sentinels for monitoring damaged DNA and mediating repair. The close cooperativity between telomere-binding proteins and DNA damage proteins is extremely important, since a compromised DNA damage response in the context of damaged telomeres leads to significant clinical manifestations, including normal aging, genome instability and premature aging syndromes, neurodegenerative diseases, and cancer. Therapeutic possibilities that have been developed for these diseases target telomeres, telomerase, or DNA damage response mediators. The interdependence of telomere maintenance and DNA damage signaling pathways is clearly evident since both entities converge toward a common goal of maintaining genomic integrity.