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.
Highlights
Maintaining genome integrity via repair of DNA damage is a key biological process required to suppress diseases
The detoxification of Reactive oxygen species (ROS) generated by metabolic reactions is crucial to avoid oxidative DNA damage and an excessive burden on the DNA repair machinery, and yet both the synthesis of antioxidants and the DNA damage response (DDR) depend on metabolism to function
Different repair pathways are involved in protecting genome integrity following DNA adduct generation: base adducts are removed by Base excision repair (BER) or nucleotide excision repair (NER) in the case of bulky adducts
Summary
Maintaining genome integrity via repair of DNA damage is a key biological process required to suppress diseases. The increased proliferation cancer cells (as depicted inofthe top cells (as depicted in the top strand) can deplete dNTP pools causing replication stress and, DNA double-strand breaks (DSBs). 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 strand) can deplete dNTP pools causing replication stress and, DNA double-strand breaks (DSBs). 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. 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. 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
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