A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification

Abstract

Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or long-patch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neuro-degeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multi-protein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER protein-protein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

Fig. 1. Classic BER pathway

Short-patch pathway (left) depicts sub-pathway initiation by glycosylase activity followed by strand scission by APE1. Gap tailoring (5’dRP lyase) and nucleotide incorporation are accomplished by pol ß. The resulting nick is ligated by a complex of XRCC1 and LigIIIα to complete the pathway. Long-patch pathway (right) depicts a sub-pathway of BER responsible for repair under conditions of 5’lesions refractory to pol ß cleavage. In this case, BER complex formation shifts, nucleotide incorporation is conducted either by pol ß or is transferred to pol-δ or pol-•. The refractory 5’ moiety is removed as part of a flap of DNA by Fen1 and re-ligation is completed by LigI.

Fig. 2. A unified model of BER

This model depicts protein complexes for repair of oxidation and alkylation base modifications and encompasses the repair of single-strand breaks, oxidative lesions processed via alternate sub-pathways such as NIR and repair initiated by the NEIL-family of bi-functional DNA glycosylases.