Human Oxoguanine Glycosylase 1 Removes Solution Accessible 8-Oxo-7,8-dihydroguanine Lesions from Globally Substituted Nucleosomes Except in the Dyad Region.

Persistent DNA damage is responsible for mutagenesis, aging, and disease. Repair of the prototypic oxidatively damaged guanine lesion 8-oxo-7,8-dihydroguanine (8-oxoG) is initiated by oxoguanine glycosylase (hOGG1 in humans). In this work, we examine hOGG1 activity on DNA packaged as it is in chromatin, in a nucleosome core particle (NCP). We use synthetic methods to generate a population of NCPs with G to 8-oxoG substitutions and evaluate the global profile of hOGG1 repair in packaged DNA. For several turns of the helix, we observe that solution accessible 8-oxoGs are sites of activity for hOGG1. At the dyad axis, however, hOGG1 activity is suppressed, even at lesions predicted to be solution accessible by hydroxyl radical footprinting (HRF). We predict this diminished activity is due to the properties of the DNA unique to the dyad axis and/or the local histone environment. In contrast to the dyad axis, the DNA ends reveal hOGG1 activity at sites predicted by HRF to be both solution accessible and inaccessible. We attribute the lack of correlation between hOGG1 activity and solution accessibility at the ends of the DNA to transient unwrapping of the DNA from the protein core, thus exposing the inward-facing lesions.