A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita

Abstract

The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC.

Keywords: WNT; dyskeratosis congenita; lithium; pulmonary fibrosis; telomerase; telomeres.

Figure 1.

A positive feedback loop connects WNT and telomere capping. In normal healthy cells, telomeres have sufficient length and shelterin occupancy to ensure the capped state, which in turn supports normal expression of WNT pathway components. This positive feedback loop is highlighted by the shaded box. As telomeres shorten, they begin to uncap, activating DNA damage responses (DDRs). The DDR upregulates miR-34a, which has many targets including WNT pathway factors, leading to the downregulation of WNT pathway factors and target genes, including those expressing the shelterins TRF1, TRF2, TIN2, and POT1. Thus, the normal mutual support between WNT signaling and telomere capping is lost. Reactivating the WNT pathway using agonists such as GSK-3 inhibitors upregulates shelterins, which promote telomere capping, thus restoring the beneficial feedback. Furthermore, in cells that can express some telomerase (e.g., normal, but also DKC1 mutant, epithelial stem cells), upregulation of TERT by WNT (top pathway) can elevate telomerase activity, thus lengthening telomeres and further promoting capping.

Figure 2.

Uncapped telomeres in one Tert^+/− parent might explain homeotic pathologies in G1 Tert^−/− mice. Park et al. (Ref. 42) described developmental transformations in the axial skeletons of half of their G1 Tert^−/− mice reminiscent of those seen in Wnt3a-deficient mice, but these changes were not seen in another study using a different cohort of mice (Ref. 43). These transformations might be explained by the presence of a sporadically generated partially uncapped telomere in the germline of one of the Tert^+/− parents. Fifty percent of the progeny would inherit this defective telomere, which might be sufficient to suppress WNT expression at a critical period of development, leading to the skeletal transformations.

Figure 3.

WNT pathway mutations underlie vitreoretinopathies that have phenotypic overlap with pathologies seen in the DC spectrum diseases. Exudative retinopathies are a component of two telomere disorders (Coats plus and Revesz syndrome), and their retinal appearance is similar to that observed in familial exudative vitreoretinopathy (FEVR) and Coats’ disease. FEVR is caused by mutations in genes encoding a WNT signaling pathway (LRP5, FRZD4, TSPAN12, RCBTB1, and CTNNB1 (β-catenin)) utilized by the NORRIN protein, and Coats’ diseases is associated with mutations in NORRIN and RCBTB1. It is therefore possible that the retinopathies in telomere disorders are caused by inhibition of WNT pathway activity induced by telomere dysfunction.

Figure 4.

Optimization of telomere length and capping. Cancer risk has a U-shaped relationship to telomere length. Telomeres that are too short lead to end-to-end fusions, the engagement of the senescence-associated secretory phenotype (SASP), and immunosenescence, each of which can have procarcinogenic effects. On the other side, when telomeres are too long, cells that acquire oncogenic mutations can bypass apoptosis and senescence programs that shortened telomeres would normally engage, also promoting cancer. We propose that the elevated cancer risk in DC is caused by telomeres that are too short. By restoring optimal telomere lengths and capping, cancer risk in DC might be reduced.