Abstract
Nowadays CHK2 mutation is studied frequently in hereditary breast and ovarian cancer patients in addition to BRCA1/BRCA2. CHK2 is a tumor suppressor gene that encodes a serine/threonine kinase, also involved in pathways such as DNA repair, cell cycle regulation and apoptosis in response to DNA damage. CHK2 is a well-studied moderate penetrance gene that correlates with third high risk susceptibility gene with an increased risk for breast cancer. Hence before planning large population study, it is better to scrutinize putative functional SNPs of CHK2 using different computational tools. In this study, we have used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of CHK2 protein that might be causing this disease. Computational analysis was performed by different in silico tools including SIFT, Align GVGD, SNAP-2, PROVEAN, Poly-Phen-2, PANTHER, PhD-SNP, MUpro, iPTREE-STAB, Consurf, InterPro, NCBI Conserved Domain Search tool, ModPred, SPARKS-X, RAMPAGE, Verify-3D, FT Site, COACH and PyMol. Out of 78 nsSNP of human CHK2 gene, seven nsSNPs were predicted functionally most significant SNPs. Among these seven nsSNP, p.Arg160Gly, p.Gly210Arg and p.Ser415Phe are highly conserved residues with conservation score of 9 and three nsSNP were predicted to be involved in post translational modification. The p.Arg160Gly and p.Gly210Arg may interfere in phosphopeptide binding site on FHA conserved domain. The p.Ser415Phe may interfere in formation of activation loop of protein-kinase domain and might interfere in interactions of CHK2 with ligand. The study concludes that mutation of serine to phenylalanine at position 415 is a major mutation in native CHK2 protein which might contribute to its malfunction, ultimately causing disease. This is the first comprehensive study, where CHK2 gene variants are analyzed using in silico tools hence it will be of great help while considering large scale studies and also in developing precision medicines related to these polymorphisms in the era of personalized medicine.
Highlights
Of all cancers, one of the main cause of cancer related deaths is breast cancer among women worldwide, with 5% to 10% of cases being due to hereditary risk [1]
The CHK2 gene investigated in the present study was retrieved from dbSNP database
It contained a total of 13929 single nucleotide polymorphism (SNPs) out of which 753 are missense, 105 are frame shift, 642 in 5’UTR, 55 in 3’ UTR, 50 nonsense, 13062 intronic, 50 stop gained, 19 in 3’ splice site, 24 in 5’ splice site and 266 in coding synonymous SNPs (Fig 1)
Summary
One of the main cause of cancer related deaths is breast cancer among women worldwide, with 5% to 10% of cases being due to hereditary risk [1]. Human CHK2 gene is a tumor suppressor gene, located on long arm of chromosome 22 at q12.1 and encoded by CHK2 serine/ threonine kinase. CHK2 is activated by the kinases ATM and ATR in response to DNA double-strand breaks or replicative stress [5] These proteins catalyze the phosphorylation of threonine 68 of CHK2 causing its transient dimerization via the FHA domain leading to CHK2 trans-autophosphorylation and its full activation. Variant p.Ile157Thr, present in 5.3% of the Finnish population and in 4.8% of the Polish population, confers a relative risk of breast cancer of 1.5 [14, 15]. Impact of missense variants on protein function is not known fully, substitutions in the FHA domain and the kinase domain have been shown to abolish activity [17,18,19]
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