A metal ion-dependent mechanism promoting gain of function in NEIL1 variants

PURPOSE: leads to increased IR cytotoxicity. Previous analyses of a single nucleotide polymorphic (SNP) variant of NEIL1, Thr103Ala (T103A), revealed compromised catalytic activities. This investigation was designed to determine the mechanisms underlying the deficiencies of T103A. MATERIALS AND METHODS: Mutant and variant NEIL1 enzymes were constructed and characterized for their ability to catalyze incision of DNAs containing site-specific base damages. Molecular dynamics (MD) simulations of wild-type (WT) and T103A variant NEIL1 using the NEIL1 crystal structure, addressed mechanisms conferring catalytic activity changes. RESULTS: hexahydrate coordinated to carbonyl oxygens of loop residues dampens loop dynamics. CONCLUSION: presence being transmitted over a distance greater than 26 Å to the NEIL1 active site.