Differential Ability of Five DNA Glycosylases to Recognize and Repair Damage on Nucleosomal DNA

Damage to genomic DNA leads to mutagenesis and disease. Repair of single base damage is initiated by DNA glycosylases, the first enzymes in the base excision repair pathway. Although eukaryotic packaging of chromosomal DNA in nucleosomes is known to decrease DNA glycosylase efficiency, the impact on individual glycosylases is unclear. Here, we present a model system in which we examine the repair of site-specific base damage in well-characterized nucleosome core particles by five different DNA glycosylases. We find that DNA glycosylase efficiency on nucleosome substrates depends not only on the geometric orientation of the damaged base but also on its identity, as well as on the size, structure, and mechanism of the glycosylase. We show via molecular modeling that inhibition of glycosylase activity is largely due to steric obstruction by the nucleosome core.