Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Modified DNA bases arise from incorporated altered nucleotides or damage to existing bases.
• Enzymes play a crucial 'sanitizing' role by preventing the incorporation of noncanonical bases.
• Understanding the catalytic mechanisms of these enzymes is vital for DNA integrity.

Purpose of the Study:

• To review and detail enzymes involved in preventing modified DNA base incorporation.
• To compare the structural and kinetic properties of different classes of sanitizing enzymes.
• To elucidate the catalytic mechanisms and evolutionary convergence of these DNA repair enzymes.

Main Methods:

• Focus on high-resolution structural studies of sanitizing enzymes.
• Comparative analysis of protein folds and active site architectures.
• Examination of catalytic mechanisms, including nucleophilic attack sites and cofactor roles.

Main Results:

• Two main classes of sanitizing deoxyribonucleoside triphosphate pyrophosphatases identified based on nucleophilic attack site (α- vs. β-phosphorus).
• Distinct coordination patterns of phosphate groups, metal ion cofactors (Mg2+), and nucleophilic water observed between the two classes.
• Enzymes utilize different catalytic strategies within diverse protein folds, illustrating convergent evolution.

Conclusions:

• Structural and mechanistic diversity exists among DNA sanitizing enzymes.
• These enzymes represent a compelling case study of convergent evolution in biological systems.
• Understanding these mechanisms provides insights into maintaining genomic stability.