No abstract

The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It comprises six proteins, namely TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. All of these assemble together to form a complex with double strand and single strand DNA repeats at the telomere. Such an association contributes to telomere stability and its protection from undesirable DNA damage control-specific responses. However, any alteration in the structure and function of any of these proteins may lead to undesirable DNA damage responses and thus cellular senescence and death. In our review, we throw light on how mutations in the proteins belonging to the shelterin complex may lead to various malfunctions and ultimately have a role in tumorigenesis and cancer progression.

A major challenge remaining in drug design efforts towards protein kinase is due to the development of drug resistance initiated by the missense mutations in the kinase catalytic domain. Gain or loss of function mutations in the REarranged during Transfection (RET) tyrosine kinase gene have been associated with the development of a wide range of human associated cancers and Hirschsprung's disease. However, to what extent these mutations might affect bio-molecular functions remains unclear. In this article, the functionally significant mutations in RET were screened with the aid of various sequence and structure based in silico prediction methods. We mapped the deleterious mutants, modelled mutant proteins and deciphered the impact of mutations on drug binding mechanisms in the RET crystal structure of PDB ID: with the potential inhibitor vandetanib by docking analysis. Furthermore, molecular dynamics simulations were undertaken to understand the mechanistic action of cancer associated mutations in altering the protein kinase structure, dynamics, and stability. According to our results, the overall effect of V804M, M918T and S922Y were destabilizing and mostly alter the electrostatic component of the binding energy. Specifically, the mutation of gatekeeper residue valine 804 present in the ATP binding pocket affects the protein stability and confers resistance to the drug vandetanib, which was consistent with previously published experimental results. Overall, our findings may provide useful structural insights for in-depth understanding of the molecular mechanism underlying RET mutation and developing effective drugs.

Background: Enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of Polycomb Repressor Complex 2. PRC2 catalyzes methylation of H3K27me and it silences specific gene transcriptions. EZH2 is known to play a vital role in cancer initiation, development, progression, metastasis, and drug resistance. The expression of EZH2 is regulated by a variety of oncogenic transcription factors, tumor suppressor micro-RNAs, and cancer-associated non-coding RNAs. Post-translational modifications also control EZH2 activity. The altered expression of EZH2 has major implication in altering cellular plasticity and, hence, understanding various deleterious mutations can help comprehend its role in cancer metastasis. Objectives: The aim of this study is to summarize the data from COSMIC into useful information from the perspective of severity of the mutations in EZH2 and their contributory role as a potential biomarker in diagnosis and therapeutics associated cancers. Methods: Data mining was carried out for various SNPs in EZH2 SET domain from COSMIC, and the severity of each mutation on the functionality of the enzyme was analyzed, using multiple online in-silico tools. The frequently deleterious SNPs were further subjected to advanced tools to understand the changes which render the enzyme functionally erratic during cancer. Results:The results obtained enhanced the understanding of EZH2 mutation and predicted the plausible biomarkers that could be targeted for the purpose of diagnosis and therapeutics. About 14 prospective biomarkers for various cancers were identified and, further, their role in altering the EZH2 function was discussed. Conclusions:The various predictive and prognostic impacts of these SNPs in the selected residues are discussed which can be efficiently targeted for an improved cancer diagnosis and designing appropriate treatment strategies.