Base excision repair in chromatin: Insights from reconstituted systems

• BER is a mechanism for repair of a variety of small modifications on DNA bases.
• The initial step in BER involves recognition and excision of a damaged or aberrant base by a specific DNA glycosylase, with remaining steps performed by common enzymes.
• While some BER may be coupled to ATP-dependent remodeling in vivo, numerous studies indicate that may of the BER enzymes can process substrates in nucleosomes.
• Both orientation of the damaged base with respect to the histone surface and sequence-specific motility of the DNA within the nucleosome dictate accessibility to BER enzymes.

The process of base excision repair has been completely reconstituted in vitro and structural and biochemical properties of the component enzymes thoroughly studied on naked DNA templates. More recent work in this field aims to understand how BER operates on the natural substrate, chromatin [1] and [2]. Toward this end, a number of researchers, including the Smerdon group, have focused attention to understand how individual enzymes and reconstituted BER operate on nucleosome substrates. While nucleosomes were once thought to completely restrict access of DNA-dependent factors, the surprising finding from these studies suggests that at least some BER components can utilize target DNA bound within nucleosomes as substrates for their enzymatic processes. This data correlates well with both structural studies of these enzymes and our developing understanding of nucleosome conformation and dynamics. While more needs to be learned, these studies highlight the utility of reconstituted BER and chromatin systems to inform our understanding of in vivo biological processes.