Abstract
DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism; including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.
Highlights
DNA repair and metabolic pathways are vital to maintain cellular homeostasis
Metabolic products from glycolysis, such as L- and D-lactate play a role in DNA repair by decreasing chromatin compaction and subsequently increasing transcription of key genes involved in DNA double-strand breaks (DSBs) repair (Wagner et al, 2015)
It must be considered that this link, and the peer reviewed studies supporting the link, have predominantly occurred in cancer cell lines and studies
Summary
DNA repair and metabolic pathways are vital to maintain cellular homeostasis. DNA repair proteins can maintain genomic stability following exposure to exogenous and endogenous genotoxic insults. Several independent studies have suggested novel roles for glycolytic proteins in DNA repair pathways, largely based on the observation that several glycolytic proteins, including Hexokinase II, Fumarase and ATP-citrate lyase (ACLY), migrate to the nucleus following exposure to genomic stress (van Vugt, 2017; Ohba et al, 2020; Hitosugi et al, 2012; Yuan et al, 2010). Several studies have suggested glycolysis may be involved in maintaining genome stability, given that the glycolytic pathway provides metabolites which play an essential role in DNA metabolism. We will review the peerreviewed evidence linking metabolism and DNA repair and how these processes may lead to radio- and chemo-resistance in tumor cells
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