BERing the burden of damage: Pathway crosstalk and posttranslational modification of base excision repair proteins regulate DNA damage management

Abstract

DNA base damage and non-coding apurinic/apyrimidinic (AP) sites are ubiquitous types of damage that must be efficiently repaired to prevent mutations. These damages can occur in both the nuclear and mitochondrial genomes. Base excision repair (BER) is the frontline pathway for identifying and excising damaged DNA bases in both of these cellular compartments. Recent advances demonstrate that BER does not operate as an isolated pathway but rather dynamically interacts with components of other DNA repair pathways to modulate and coordinate BER functions. We define the coordination and interaction between DNA repair pathways as pathway crosstalk. Numerous BER proteins are modified and regulated by post-translational modifications (PTMs), and PTMs could influence pathway crosstalk. Here, we present recent advances on BER/DNA repair pathway crosstalk describing specific examples and also highlight regulation of BER components through PTMs. We have organized and reported functional interactions and documented PTMs for BER proteins into a consolidated summary table. We further propose the concept of DNA repair hubs that coordinate DNA repair pathway crosstalk to identify central protein targets that could play a role in designing future drug targets.

Keywords: Base excision repair BER; DNA damage; DNA pathway crosstalk; DNA repair hubs; Post-translational modifications PTMs.