Challenges for base excision repair enzymes: Acquiring access to damaged DNA in chromatin

Repair of damaged DNA plays a crucial role in maintaining genomic integrity and normal cell function. The base excision repair (BER) pathway is primarily responsible for removing modified nucleobases that would otherwise cause deleterious and mutagenic consequences and lead to disease. The BER process is initiated by a DNA glycosylase, which recognizes and excises the target nucleobase lesion, and is completed via downstream enzymes acting in a well-coordinated manner. A majority of our current understanding about how BER enzymes function comes from in vitro studies using free duplex DNA as a simplified model. In eukaryotes, however, BER is challenged by the packaging of genomic DNA into chromatin. The fundamental structural repeating unit of chromatin is the nucleosome, which presents a more complex substrate context than free duplex DNA for repair. In this chapter, we discuss how BER enzymes, particularly glycosylases, engage in the context of packaged DNA with insights obtained from both in vivo and in vitro studies. Furthermore, we review factors and mechanisms that can modify chromatin architecture and/or influence DNA accessibility to BER machinery, such as the geometric location of the damage site, nucleosomal DNA unwrapping, histone post-translational modifications, histone variant incorporation, and chromatin remodeling.