Our DNA is constantly exposed to both endogenous and exogenous sources of damage that necessitates multiple repair mechanisms to protect the genetic information it contains. For instance, the base excision repair (BER) pathway targets modified nucleobases, removes the nucleotide, and replaces it with the appropriate unmodified nucleotide in its place. BER is initiated by glycosylases, which recognize and remove modified nucleobases. Glycosylases have the challenge of locating specific lesions quickly and efficiently among a genome of undamaged DNA. Previous studies on free duplex have shown that this efficiency might be attributed to a glycosylase’s processivity, or its ability to locate and excise multiple modified nucleobases in a single binding event. There are two main mechanisms of processivity between lesion sites: DNA sliding and hopping. Sliding is characterized by the glycosylase’s close association to the DNA by following the phosphate backbone. Hopping is characterized by small dissociations from the DNA with a high probability of re-associating. The relative contribution of each mechanism depends on the location and distance between the lesion sites within the free duplex.<br/> <br/>Thus far, the characterization of glycosylase processivity has only been on free duplex substrates. However, genomic DNA is packaged in an organized, compact manner to fit in the cell nucleus. Our goal is to determine how glycosylase processivity is influenced by DNA compaction. We use the first order of DNA packaging, the nucleosome core particle (NCP), to study the ability of uracil DNA glycosylase (UDG) to recognize and remove two site-specific uracil lesions within an NCP DNA substrate.<br/>

Characterizing uracil DNA glycosylase processivity in nucleosome core particles

256th National Meeting (2018)

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