Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact.

Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact.

Publication date: Feb 04, 2019

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.

Open Access PDF

Badgujar, N.V., Tarapara, B.V., and Shah, F.D. Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact. 05159. 2019 PLoS One (14):8.

Concepts Keywords
3D Branches of biology
Activation Loop Breast cancer
Apoptosis Tumor suppressor genes
BRCA1 Tumor markers
BRCA2 CHEK2
Breast Transcription factors
Breast Cancer BRCA2
CHK2 BRCA1
FHA RELA
Gene Penetrance
Kinase Protein kinase
Ligand SNP
Mutation Apoptosis
NCBI
Penetrance
Personalized Medicine
PhD
Phenylalanine
Polymorphisms
Post Translational Modification
Protein
PyMol
Serine
SIFT
SNP
SNPs
Threonine
Tumor Suppressor

Semantics

Type Source Name
gene UNIPROT RRAD
gene UNIPROT NSUN2
gene UNIPROT LONP2
gene UNIPROT DELE1
gene UNIPROT XIRP1
gene UNIPROT TALDO1
gene UNIPROT LRSAM1
disease MESH point mutations
disease MESH genetic diseases
gene UNIPROT CPSF4
gene UNIPROT KRAS
disease DOID CML
disease DOID CML
gene UNIPROT CISH
gene UNIPROT RENBP
gene UNIPROT TNIP1
gene UNIPROT KCNK6
gene UNIPROT TP53
disease MESH syndromes
disease MESH Li Fraumeni syndrome
disease MESH multi
drug DRUGBANK L-Alanine
disease MESH tryptophan
gene UNIPROT UAP1
drug DRUGBANK Imidacloprid
drug DRUGBANK ATP
gene UNIPROT BTG3
gene UNIPROT EAF2
drug DRUGBANK L-Valine
drug DRUGBANK L-Asparagine
drug DRUGBANK Alpha-Linolenic Acid
gene UNIPROT TYR
drug DRUGBANK L-Tyrosine
gene UNIPROT TBPL1
gene UNIPROT TYRP1
drug DRUGBANK L-Tryptophan
pathway BSID Translation
drug DRUGBANK L-Cysteine
gene UNIPROT RERE
gene UNIPROT ABL2
drug DRUGBANK L-Arginine
drug DRUGBANK Glutamic Acid
drug DRUGBANK L-Leucine
drug DRUGBANK L-Isoleucine
drug DRUGBANK L-Lysine
drug DRUGBANK Glycine
gene UNIPROT ASIP
gene UNIPROT ASPA
gene UNIPROT ROPN1L
gene UNIPROT A1CF
gene UNIPROT ATG5
drug DRUGBANK L-Aspartic Acid
gene UNIPROT MET
gene UNIPROT SLTM
drug DRUGBANK Methionine
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT MAP6
gene UNIPROT CALM1
gene UNIPROT SCN8A
disease MESH dif
gene UNIPROT CDA
gene UNIPROT NPPA
disease MESH community
gene UNIPROT MAPT
gene UNIPROT SNRPB
gene UNIPROT REST
gene UNIPROT PHPT1
drug DRUGBANK Amino acids
gene UNIPROT BPIFA4P
gene UNIPROT SLC26A5
gene UNIPROT NR4A3
gene UNIPROT MAF
gene UNIPROT PTPRF
disease MESH men
gene UNIPROT SERPINA2
gene UNIPROT ATR
gene UNIPROT ANTXR1
gene UNIPROT ATM
gene UNIPROT MAGEE1
gene UNIPROT LAT2
disease DOID cancer
disease MESH cancer
gene UNIPROT RXFP2
drug DRUGBANK L-Phenylalanine
gene UNIPROT SLC35G1
gene UNIPROT DESI1
gene UNIPROT PDC
gene UNIPROT SNAP25
drug DRUGBANK Tropicamide
gene UNIPROT LARGE1
disease MESH DNA damage
pathway BSID Apoptosis
pathway BSID DNA Repair
drug DRUGBANK L-Threonine
drug DRUGBANK Serine
gene UNIPROT BRCA2
gene UNIPROT BRCA1
disease DOID ovarian cancer
disease MESH ovarian cancer
gene UNIPROT IMPACT
pathway BSID Breast cancer
disease DOID breast cancer
disease MESH breast cancer
gene UNIPROT CHEK2

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