Abstract
Overexpression of telomerase is one of the hallmarks of human cancer. Telomerase is important for maintaining the integrity of the ends of chromosomes, which are called telomeres. A growing number of human disease syndromes are associated with organ failure caused by mutations in telomerase (hTERT or hTR). Mutations in telomerase lead to telomere shortening by decreasing the stability of the telomerase complex, reducing its accumulation, or directly affecting its enzymatic activity. In this work, potential human telomerase mutations were identified by a systematic computational approach. Moreover, molecular docking methods were used to predict the effects of these mutations on the affinity of certain ligands (C_9i, C_9k, 16A, and NSC749234). The C_9k inhibitor had the best binding affinity for wild-type (WT) telomerase. Moreover, C_9i and C_9k had improved interactions with human telomerase in most of the mutant models. The R631 and Y717 residues of WT telomerase formed interactions with all studied ligands and these interactions were also commonly found in most of the mutant models. Residues forming stable interactions with ligands in molecular dynamics (MD) were traced, and the MD simulations showed that the C_9k ligand formed different conformations with WT telomerase than the C_9i ligand.
Highlights
Telomerase, a ribonucleoprotein (RNP), acts as a reverse transcriptase that synthesises telomeric DNA repeats at the ends of chromosomes[1]
The key active-site residues in the TERT catalytic subunit of Tribolium castaneum telomerase have been published by Gillis et al in[11] (PBD: 3DU6; Fig. 1A)
We used the TERT catalytic subunit of the human telomerase model[19] and defined/predicted the active-site residues based on T. castaneum telomerase structure[11,33,34,35] (Fig. 1A)
Summary
Telomerase, a ribonucleoprotein (RNP), acts as a reverse transcriptase that synthesises telomeric DNA repeats at the ends of chromosomes[1]. The ability of a telomere to provide genomic stability decreases over time, owing to both the natural loss of telomeric structure with each cell division (the end replication problem) and the loss of telomerase activity This process leads to ageing[4,5]. The C-terminal domain is required for telomerase-specific activity other than catalytic function and in the telomeric nucleotide addition process[24,25]. The catalytic domain of the enzyme complex[25,26,27,28] Inherited mutations in both human TERC (the template region of an integral RNA component) and human TERT part of protein lead to rare bone marrow failure syndromes, autosomal dominant dyskeratosis congenita, and acquired aplastic anaemia[28,29,30,31]. Residues V658, K659, R669, V867, R972, and K973 of human model were selected in the current study because previous studies have shown the importance of these residues in different biological functions of human telomerase (Fig. 1A)[19]
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