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From bacteria to mammals, DNA mismatch repair (MMR) pathway plays an essential role in eliminating mismatched nucleotides and insertion-deletion mismatches during the process of DNA replication. Among many of the proteins which participate in the mismatch repair process, proliferating cell nuclear antigen (PCNA) remains the principal conductor at the replication fork. The pol30-201 and pol30-204 are the two mutated alleles which encode for C22Y and C81R mutant forms of PCNA proteins. We performed long term molecular dynamics (MD) simulations analysis (0.8 μs) to understand the dynamic behavior and alterations in the structure of wild type and mutated forms of PCNA at the atomic level. We observed changes in the structural characteristics like length, radius, rise per residue of alpha helices in both the mutated forms of PCNA. Apart from it, disfigurement of the charge distribution which effects binding with the dsDNA due to mutant C22Y and other structural perturbations were also seen in regions significant for the formation of a biologically active trimeric form of PCNA due to mutant C81R. Our analysis of native and mutated forms of PCNA provides an insight into the essential structural and functional features required for proper and well-coordinated DNA mismatch repair process and consequences of the mutation leading to an impaired process of MMR. These structural characteristics are fundamental for the MMR process and hence our analysis likely contributes to or presents the novel mechanism involved in the process of MMR.Communicated by Ramaswamy H. Sarma.

Citation

Vijay Bhardwaj, Rituraj Purohit. Computational investigation on effect of mutations in PCNA resulting in structural perturbations and inhibition of mismatch repair pathway. Journal of biomolecular structure & dynamics. 2020 Apr;38(7):1963-1974

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PMID: 31138032

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