A role for sister telomere cohesion in telomere elongation by telomerase

Abstract

T elomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC), a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and, further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.

Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy

“…These observations have led to a model whereby defective sister telomere cohesion impairs telomerase mediated elongation, resulting in the extreme telomere shortening observed in TINF2 mutation carriers. 65, 66 While the existing data are consistent with a loss-of-function mechanism, the failure to identify patients with nonsense or frameshift mutations within the N terminal region upstream of the HP1γ binding site of TIN2 suggests that the DC-cluster mutations exert a dominant negative effect. TIN2 −/− mice are embryonic lethal in both the presence and absence of telomerase, indicating that TIN2 has an essential function that is independent of telomerase-mediated telomere elongation.…”

Telomere Length Reprogramming in Embryos and Stem Cells

“…Dyskeratosis Congenita, the prototypical telomere syndrome, results from mutations in the gene encoding many of the telomere maintenance genes, including TERT , TERC , TINF2 , and DKC [16, 22–27]. This disorder manifests in tissues prone to high turnover, such as liver, fingernail beds, mucous membranes, and the hematopoietic system [16].…”

Inter-telomeric recombination is present in telomerase-positive human cells

“…TIN2 has been shown to bind heterochromatin protein 1 (HP1), which increases telomere cohesion. 48 Such recombination. However, if potent antitelomerase inhibitors become available in the clinical setting, this might become an issue of concern.…”