Molecular mechanisms of telomere biology disorders

Abstract

Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita (DC), pulmonary fibrosis (PF) and aplastic anemia (AA), is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin, and the telomerase RNA maturation component PARN, affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of DC mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pin-point disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.

Molecular Aspects of Senescence and Organismal Ageing—DNA Damage Response, Telomeres, Inflammation and Chromatin

“…Telomeropathies are a group of disorders resulting among many other symptoms in very short telomere length and disease anticipation. They are caused by a loss of function in genes required for telomere maintenance [ 65 , 66 ]. The most severe telomeropathies are dyskeratosis congenita, pulmonary fibrosis and aplastic anaemia [ 67 ].…”

“…The most severe telomeropathies are dyskeratosis congenita, pulmonary fibrosis and aplastic anaemia [ 67 ]. It can result in premature ageing and high probability of cancer or leukaemia development (see [ 65 , 66 , 68 , 69 ] for review).…”

The clinical and functional effects ofTERTvariants in myelodysplastic syndrome

“…In the MDS cohort, we sequenced the TERT coding region (exons [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and known germline single nucleotide polymorphisms (SNPs). In the NHL cohort, we sequenced TERT in DNA extracted from mobilized whole peripheral blood samples.…”

“…Germline pathogenic variants affecting telomerase-and telomere-associated proteins cause a global impairment in telomere maintenance and short telomeres in all tissues. 1,[9][10][11] Individuals with dyskeratosis congenita (DC), an early-onset syndromic presentation of a telomere biology disorder, have characteristic mucocutaneous features, bone marrow failure, 2,12 and a markedly increased risk of developing MDS or acute myeloid leukemia. 2,4,13,14 In contrast, adult patients with a telomere biology disorder more frequently present with aplastic anemia, [15][16][17] idiopathic pulmonary fibrosis, [18][19][20][21][22][23] and liver cirrhosis.…”

An Update of Molecular Basis of Telomere Biology Diseases

“…Especially, why is dyskeratosis congenita considered a ribosomopathy? Whatsort of role ribosomes have in this disease?To answer to these questions we started from a piece of data of which we have a match in all DC's forms: patients 'cells, especially those with a high turn-over, present a telomere shortening and a ribosomes 'synthesis dysfunctions[61] [91]. These two structures, telomeres and ribosomes, that seem to be very far from a localization point of view, are related from a biogenesis point of view.…”