Investigation of deleterious effects of nsSNPs in the <i>POT1</i> gene: a structural genomics‐based approach to understand the mechanism of cancer development

Amir, Mohd.; Kumar, Vijay; Mohammad, Taj; Dohare, Ravins; Hussain, Afzal; Rehman, Tabish; Alam, Perwez; Alajmi, Mohamed F.; Islam, Asimul; Ahmad, Faizan; Hassan, Md. Imtaiyaz

doi:10.1002/jcb.28312

Cited by 35 publications

(19 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PolyPhen 2.0 calculates the impact of point mutations on the structure of protein as well as its effects on phenotype. A detailed description of methods for deleterious nsSNP prediction is provided in our earlier communication (Amir et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome

Amir

Mohammad

Kumar

et al. 2019

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

The human CST complex (CTC1–STN1–TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.

show abstract

Section: Methodsmentioning

confidence: 99%

Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome

Amir

Mohammad

Kumar

et al. 2019

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The number of glycine residues is 15 and the number of proline residues is 9. 25 Then the models generated by I-TASSER in PDB format were visualized using PyMOL. 26…”

Section: Bendahou Et Almentioning

confidence: 99%

Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

et al. 2020

View full text Add to dashboard Cite

Introduction: The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas. Methods: In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 ( IDH1) and isocitrate dehydrogenase 2 ( IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53. Results: We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M. Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein. Conclusion: In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.

show abstract

“…Telomere dysfunction may also be a resultant of altered telomere-associated proteins that are also essential for regular end-capping function (187, 188). For example, mutations in the C-terminal of POT1 can initiate genomic instability permissive for tumourigenesis (189).…”

Section: Role Of Telomeres and Telomerase In Pre-malignant And Malignmentioning

confidence: 99%

Telomerase and Telomeres in Endometrial Cancer

et al. 2019

View full text Add to dashboard Cite

Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the “end replication problem” as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80–90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.

show abstract

Investigation of deleterious effects of nsSNPs in the POT1 gene: a structural genomics‐based approach to understand the mechanism of cancer development

Cited by 35 publications

References 72 publications

Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome

Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome

Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

Telomerase and Telomeres in Endometrial Cancer

Contact Info

Product

Resources

About