Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Abstract

Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

Keywords: DNA damage; DNA damage response; DNA repair; high-throughput technologies; metabolism.

Figure 1

Interplay between cellular metabolism and the DNA damage response in cancer. (a) Metabolic reactions generate DNA damage. Toxic metabolites, such as alkylating agents and aldehydes, which are produced by lipid peroxidation and other metabolic pathways, can generate DNA adducts. Reactive oxygen species (ROS), mainly produced by oxidative phosphorylation, generate oxidative DNA damage. ROS can be detoxified by antioxidants, such as glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). The increased proliferation of cancer cells (as depicted in the top strand) can deplete dNTP pools causing replication stress and, consequently, DNA double-strand breaks (DSBs). Imbalances in nucleotide pools (as depicted in the bottom strand) cause misincorporations during replication, which can lead to mutations. (b) Metabolism is required for DNA repair. Metabolic enzymes recruit DNA repair proteins to the sites of DSBs, and the production of a local pool of nucleotides in the vicinity of DSBs is needed for accurate repair. Proteins involved in DNA adduct repair are regulated by metabolites. The dealkylases AlkB homologs 2 and 3 (ALKBH2/3) use α-ketoglutaric acid (α-KG)—produced from glutamine—as a key substrate and are inhibited by the oncometabolite 2-hydroxyglutarate (2HG). The enzyme aldehyde dehydrogenase 2 (ALDH2), which is involved in the degradation of aldehydes, can itself be crosslinked by this metabolite, hence reducing its activity. Poly-ADP-ribose polymerases (PARPs) and sirtuins are essential enzymes in the DNA damage response (DDR) and use the metabolite nicotinamide adenine dinucleotide (NAD⁺) as a substrate. Finally, chromatin remodeling and epigenetic marks play a crucial role in DNA repair. The production of acetyl-CoA in the vicinity of DSBs facilitates histone acetylation and BRCA1 recruitment, promoting homologous recombination (HR). On the contrary, the inhibition of the lysine specific demethylases 4A and 4B (KDM4A/B) by 2HG, fumarate, or succinate prevents histone demethylation and subsequent recruitment of HR factors.

Figure 2

Metabolism and the repair of DNA double-strand breaks. Crosstalk between metabolism and DNA repair can be classified into three categories: (a) dNTP-pool regulation is critical for DNA repair, (b) metabolic enzymes and metabolites are directly involved in DSB repair, and (c) metabolic regulation of epigenetic marks influences DNA repair.

Figure 3

Overview of currently available high-throughput technologies and approaches to discover new crosstalk between metabolism and the DNA damage response (DDR). Proteomics can be used to either quantify the abundance of proteins or post-translational modifications after DNA damage, whereas affinity purification of known DNA repair proteins can identify unknown interactors. Metabolomics can identify metabolites that modulate DNA repair. Genetic or chemical screens utilizing a variety of different readouts, described in more details in the main text, have been developed and represent a useful tool to pinpoint complex interaction networks between metabolism and DDR.