Protein-DNA interactions & DNA repair
Cells have developed elaborate repair systems to defend themselves against unwarranted and detrimental mutations in DNA. One of the central machineries that is able to uphold the integrity of cellular DNA, despite constant threats of stress from the environment. How enzymes repair DNA are specific to the given catalytic task at hand. Here, we explore two different enzymatic strategies for the repair of DNA.
1. How do DNA-repair enzymes balance stability with degradability?
- O6-alkylguanine-DNA alkyltransferase (hAGT) adopts a non-enzymatic suicide mechanism for the repair of methylated guanine bases
- It transfers the methyl adduct to itself, triggering unfolding and fast degradation
- Interactions with a key alpha helix and the alkyl adduct initiates unfolding
- Key residues play the role as a “sensor” to detect alkyl adducts and increase steric interactions (tension) between the active site and this key alpha helix to trigger release
2. How does environment influence enzyme catalysis of DNA repair proteins?
- The cleavage of the N-glycosidic bond is an important step in repairing oxidized guanine bases.
- MutY has optimized its catalytic role by convening water molecules in a unique configuration at the site of N7 protonation, facilitating the cleavage reaction.
- Using classical molecular dynamics and QM/MM molecular dynamics, we find that MutY, surprisingly, uses hydrophobic residues in combination with hydrophilic residues to tune the microenvironment into a water trap.
- Reference Publications:
- Brunk, Elizabeth, J. Samuel Arey, and Ursula Rothlisberger. Journal of the American Chemical Society 134.20 (2012): 8608-8616.
- Brunk, Elizabeth, Birgit Mollwitz, and Ursula Rothlisberger. ChemBioChem 14.6 (2013): 703-710.
- Mentes, A; Florescu, AM; Wereszczynski, J; Joyeux, M; Andricioaei I. Free energy landscape and characteristic forces for the initiation of DNA unzipping. Biophysical Journal (2015) 108, (7) 1727-1738