Single-nucleotide polymorphisms in DNA repair genes ERCC, XRCC, and MGMT and implications in glioblastoma: a pathway analysis and structural dynamics study

Genes partaking in DNA damage repair (DDR) pathways exert a key role in the progression of glioblastoma (GBM) and treatment resistance. Essential DDR genes, including XRCC, ERCC, and MGMT, are mutated in GBM, with single nucleotide variants (SNVs) clinically linked to the. However, the structural consequences and biophysical alterations to protein dynamics linked to RCC/MGMT SNVs in GBM are not well-studied. We analyzed GBM-related SNVs in XRCC2, XRCC3, ERCC2, and MGMT. Structural Alphafold models were built. Eight molecular dynamics simulation (MDS) runs for up to 100 ns were carried out via an all-atom forcefield. Structural analyses, such as H-bond, RMSD, RMSF, gyration, and SASA were evaluated. Moreover, protein-protein interactions (PPIs) and mRNA expression levels were assessed by STRING/Cytoscape. The SNVs, XRCC2 (Arg188His), XRCC3 (Thr241Met), ERCC2 (Lys751Gln), and MGMT (Leu84Phe), were associated with notable structural changes. MDS study revealed increased flexibility, compactness, as well as alterations in H-bonding and solvent exposure in mutants of several DDR pathway genes compared to wild-type RCC/MGMT proteins. The modified regional flexibility for all genes was identified by RMSF computation. Pathway analysis showed XRCC3 as the most connected hub within the DDR network. Upregulation of DDR genes, in particular XRCC2/MGMT, correlated with a poorer clinical outlook. A statistically meaningful and direct positive correlation of ERCC2 and MGMT was shown (p