Initiating base excision repair in chromatin

Abstract

The base excision repair (BER) pathway removes modified nucleobases that can be deleterious to an organism. BER is initiated by a glycosylase, which finds and removes these modified nucleobases. Most of the characterization of glycosylase activity has been conducted in the context of DNA oligomer substrates. However, DNA within eukaryotic organisms exists in a packaged environment with the basic unit of organization being the nucleosome core particle (NCP). The NCP is a complex substrate for repair in which a variety of factors can influence glycosylase activity. In this Review, we focus on the geometric positioning of modified nucleobases in an NCP and the consequences on glycosylase activity and initiating BER.

Keywords: Base excision repair; Chromatin; DNA damage; DNA repair; Glycosylase; Nucleosome.

Fig. 1.

Representations of the NCP. (A) Top view and (B) side view of the NCP represented as a spool-and-thread cartoon. The DNA is colored blue and the histone octamer core is gray. The dyad axis is indicated by a dashed orange line in (A) and an orange rod coming out of the plane of (B). The pseudosymmetry of the histone octamer about the dyad axis is indicated by the green arrow. In (C) and (D) the histone proteins are shown as ribbon diagrams and images are merged crystal structures of an NCP containing the Widom 601 DNA with a histone octamer containing N-terminal tail regions (Protein Data Bank entries 3lz0 and 1kx5, respectively). (E) Rotational positions of nucleobases relative to the histone octamer core (only one DNA strand is shown for simplicity). Outward (red), midway (purple), and inward (blue) bases are indicated.

Fig. 2.

Representation of an NCP showing an unwrapped state of one end of the DNA from the histone octamer core.