Implementation of computational approaches to explore the deleterious effects of non-synonymous SNPs on pRB protein

Abstract

Retinoblastoma 1 (RB1) is the first discovered tumor suppressor gene and recognized as the simple model system whose encoded defective protein can cause a pediatric cancer retinoblastoma. It functions as a negative regulator of the cell cycle through the interactions with members of the E2F transcription factors family. The protein of the RB1 gene (pRB) is engaged in various cell cycle processes including apoptosis, cell cycle arrest and chromatin remodeling. Recent studies on Retinoblastoma also exhibited multiple sets of point mutation in the associated protein due to its large polymorphic information in the local database. In this study, we identified the list of disease associated non-synonymous single nucleotide polymorphisms (nsSNPs) in RB1 by incorporating different computational algorithms, web servers, modeling of the mutants and finally superimposing it. Out of 826 nsSNPs, W516G and W563G were predicted to be highly deleterious variants in the conserved regions and found to have an impact on protein structure and protein-protein interaction. Moreover, our study concludes the effect of W516G variant was more detrimental in destabilizing protein’s nature as compared to W563G variant. We also found defective binding of pRB having W516G mutation with E2F2 protein. Findings of this study will aid in shortening of the expensive experimental cost of identifying disease associated SNPs in retinoblastoma for which specialized personalized treatment or therapy can be formulated.

Communicated by Ramaswamy H. Sarma

Keywords:

• Retinoblastoma
• nsSNPs
• computational analysis
• single nucleotide polymorphism (SNP)
• E2F2

Acknowledgements

No specific acknowledgment.

Disclosure statement

The authors declare that they have no competing interests.

Ethical approval

Not required.

Funding

No grant was received for this study.

Author contributions

MMR and HH conceived the study. MMR and NAZ designed the study. RI, MMR and NAZ conducted the experiments. RI and MR analyzed and interpreted the data. RI and MR wrote the original draft of the manuscript. RI, MR, NAZ and HH reviewed and edited the final manuscript. All authors approved the final manuscript.