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.

Coordination of DNA Base Excision Repair by Protein-Protein Interactions

“…The activities of the multifunctional enzyme, its expression level, and intracellular localization are regulated by its interaction with the multifunctional protein nucleophosmin (NPM1) [89]. Direct interactions of APE1 and several DNA glycosylases (TDG, NEIL2, NTH1, OGG1, and UNG2) with protein factors of nucleotide excision repair (XPC, XPG, CSB, and RPA) and homologous recombination (Rad52) have been shown to play a regulatory role in the overlapping repair pathways [90].…”

“…Posttranslational modifications (PTMs) of proteins involved in BER modulate catalytic and DNA-binding activities of individual proteins, their expression, intracellular localization, structure, and stability as well as protein-protein interactions and may therefore contribute to regulation of DNA repair either directly or indirectly. Numerous studies of PTMs and their functions in BER have been reviewed previously [90,[102][103][104][105][106]. As mentioned above, PARP1 modifies itself and binding partners with poly(ADP-ribose).…”

“…The most frequent PTMs discovered for the multifunctional protein APE1 include phosphorylation, acetylation, S-nitrosylation, S-glutathionylation, formation of disulfide bonds, and ubiquitination [90,102]. Most modifications modulate redox activity of APE1 and its regulatory function in transcription.…”

“…Acetylation of DNA glycosylase TDG weakens its interaction with APE1 and produces opposite effects on the excision activity of the enzyme toward various types of base damages; repair of damage induced by the chemotherapeutic action of 5-fluorouracil is enhanced by the TDG acetylation [90]. Based on these data, the acetylation status of TDG within tumor cells was proposed to impact the chemotherapy efficacy.…”

Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

“…While both BER and NER pathways have been conventionally associated with specific substrates, growing evidence shows a significant cooperation between these two repair mechanisms, and has recently been reviewed (Melis et al, 2013;Limpose et al, 2017;Shafirovich and Geacintov, 2017). The relevance of this potential interaction includes the fact that NER deficient (XP and CS) patients may develop developmental and neurological symptoms, related to premature aging, that can be due to endogenous lesions, such as DNA damage induced by oxidation, which are normally considered substrates for BER.…”