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

Abstract

Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation or recombination. Both the DNA and protein components of the telomere are required for this essential function, as insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are two life threatening disease manifestations in the inherited telomere biology disorder, dyskeratosis congenita. Here, we provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Lastly, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers.

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“…Furthermore, some alterations affect proteins which do not have a direct impact on telomerase but concern the telomere such the telomere maintenance complex component 1 protein (CTC1 gene) that is associated to Coats plus syndrome, which is a form of cerebroretinal microangiopathy with calcifications and cysts. Finally, mutations of the regulator of telomere elongation helicase 1 (RTEL1 gene) have been identified in patients with severe autosomal recessive DC [35] (Table 1). DC is a rare inherited disorder characterized by a typical triad of clinical manifestations: skin hyperpigmentation, oral leukoplakia and nail dystrophy [26].…”

“…The group of DC genes encompasses the core telomerase component TERT and TERC and the telomerase complex proteins coded by DKC1, WRAP53, NOP10 and NHP2 genes. Other genes include the shelterin complex TIN2 gene, CTC1 and RTEL1 genes [35] (Table 1). AA is a rare and severe bone marrow disorder characterized by hypocelullar bone marrow and low blood cell counts [109].…”

“…The symptoms that characterize the disease are chronic cough and shortness of breath due to fibrotic lesions and scarring of the lungs [40]. IPF can co-exist in patients with AA and DC [35]. Like in the aforementioned disorders, IPF patients also have shorter telomeres than age-matched controls [17].…”

“…TERT and TERC telomerase component mutations have been found in familial forms of IPF [107]. The human diseases associated with telomerase or telomere dysfunction encompass mainly the above-referred three disorders (and some related syndromes) but there are other rare diseases reported in the literature [35]. Most of them are haematological disorders, such as myelodysplatic syndrome and paroxysmal nocturnal haemoglobinuria [35].…”

“…The human diseases associated with telomerase or telomere dysfunction encompass mainly the above-referred three disorders (and some related syndromes) but there are other rare diseases reported in the literature [35]. Most of them are haematological disorders, such as myelodysplatic syndrome and paroxysmal nocturnal haemoglobinuria [35]. In cases of myelodysplastic syndrome, mutations are considered an extremely rare event and were described in TERC coding region and its promoter [17].…”