Association between PARP-1 V762A polymorphism and breast cancer susceptibility in Saudi population

Abstract

Genetic aberrations of DNA repair enzymes are known to be common events and to be associated with different cancer entities. Aim of the following study was to analyze the genetic association of rs1136410 (Val762Ala) in PARP1 gene with the risk of breast cancer using genotypic assays and insilico structural predictions. Genotypic analysis of individual locus showed statistically significant association of Val762Ala with increased susceptibility to breast cancer. Protein structural analysis was performed with Val762Ala variant allele and compared with the predicted native protein structure. Protein prediction analysis showed that this nsSNP may cause changes in the protein structure and it is associated with the disease. In addition to the native and mutant 3D structures of PARP1 were also analyzed using solvent accessibility models for further protein stability confirmation. Taken together, this the first study that confirmed Val762Ala variant has functional effect and structural impact on the PARP1 and may play an important role in breast cancer progression in Saudi population.

Figure 1. The crystal structure domain of human recombinant poly (ADP-ribose) Polymerase (PARP).

(a) Crystal structure domain of the human PARP1 protein structural changes in the regions due to mutation. (b) Wild type structure of PARP1 domain Chain ‘A’ have a point mutation αHelix-5 VAL762 (blue) in a stick representation of the helix region. (c) Mutant type structure of PARP1 domain Chain ‘A’ have a mutation αHelix-5 ALA762 (red) a stick representation of the helix region. (d) Wild and Mutant type structures superimposed of PARP1 domain Chain ‘A’ have wild type residue αHelix-5 VAL762 (red) and mutant residue αHelix-5 ALA762 (blue). Figures (a-d) were made by using CCP4/QTMG.

Figure 2. The dbSNP were used to recognize the protein encoded by PARP1 gene (PDB ID: 1uk0) and identified a single mutation residue position.

The Z-score, which indicates overall model quality was -9.51 in (black color). The Z-score plot from the different sources (X-ray, and NMR) was distinguished by various colors (X-ray in pale blue and NMR in dark blue color).

Figure 3. The MD simulation showing truncated octahedron boundary explicit water solvated.

The molecular dynamic simulation used in system calculation are, (a) water box surround the entire protein in middle. The visual inspection also allow to identify the side chain of the histidine residue involved in the hydrogen bonding with surrounding molecules and in that case the δ nitrogen of the histidine (HSB;1-4) was protonated residue.

Figure 4. Relative PARP1 mRNA expression in different grades of breast cancer.

(Ct values are plotted ±SEM).