Telomeres: protecting chromosomes against genome instability

Key Points Telomeric proteins control telomere length and telomere integrity. The six bona fide telomeric binding proteins form shelterin, a complex that maintains chromosome end integrity. Telomere dysfunction can be caused by loss of telomeric repeats or by loss of protective features, both of which are essential for telomere function. Functional telomeres interact with the DNA damage machinery, but the machinery is prevented from processing these ends. Dysfunctional telomeres are recognized as damage and repaired. Repair of dysfunctional telomeres by fusion propels cells into breakage–fusion–bridge cycles, resulting in unequal distribution of genetic material into daughter cells and, therefore, genome instability. Telomere dysfunction and the failure to maintain telomere length is emerging as being the cause of several diseases. An unstable genome is a hallmark of many cancer cells. Telomeres prevent the ends of linear chromosomes from being recognized as damaged DNA, thus protecting them from DNA repair mechanisms and inhibiting the breakage–fusion–bridge cycles that cause genome instability. The natural ends of linear chromosomes require unique genetic and structural adaptations to facilitate the protection of genetic material. This is achieved by the sequestration of the telomeric sequence into a protective nucleoprotein cap that masks the ends from constitutive exposure to the DNA damage response machinery. When telomeres are unmasked, genome instability arises. Balancing capping requirements with telomere replication and the enzymatic processing steps that are obligatory for telomere function is a complex problem. Telomeric proteins and their interacting factors create an environment at chromosome ends that inhibits DNA repair; however, the repair machinery is essential for proper telomere function.