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Review
. 2021 Mar 23:9:633305.
doi: 10.3389/fcell.2021.633305. eCollection 2021.

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Thais Sobanski  1 , Maddison Rose  1 , Amila Suraweera  1 , Kenneth O'Byrne  1   2 , Derek J Richard  1 , Emma Bolderson  1   2
Affiliations
Review

Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Thais Sobanski et al. Front Cell Dev Biol. .

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.

Keywords: DNA repair; cell metabolism; glycolysis; homologous recombination; non-homologous end-joining; tumor metabolic reprogramming; warburg effect.

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Conflict of interest statement

KO and DR are founders of CARP Pharmaceuticals. EB, DR, and KO are founders of Carpe Vitae Pharmaceuticals. EB, KO, and DR are inventors on patent applications filed by Queensland University of Technology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The relationship between the Pentose Phosphate Pathway and DNA damage and repair. The PPP comprises of two phases known as the oxidative and non-oxidative phases. The oxidative phase is responsible for the conversion of glucose-6-phosphate to ribose-5-phosphate, which releases NADPH to maintain the cellular redox balance and also reduces oxidative damage. In the non-oxidative phase, the activity of a key enzyme, G6PD is stimulated by ATM to promote the production of NADPH and nucleotide synthesis. The activation of G6PD is essential to maintain a reduced cellular environment and also synthesises nucleotide precursors for DNA damage repair. This figure was created with BioRender.com.
FIGURE 2
FIGURE 2
A schematic representation of the Ataxia-Telangiectasia Mutated- (ATM) and DNA-Dependent Kinase- (DNA-PK) mediated regulation of metabolic processes after DNA Damage. ATM activates multiple downstream proteins regulating cell cycle arrest, DNA repair and cellular metabolism. ATM activates the tumor suppressor p53 which decreases GLUT recruitment, glycolysis, and dNTP production. ATM non-canonical function is essential for repairing mitochondrial genome defects to maintain mitochondrial homeostasis. For maintenance of energy production ATM activates AKT to promote glucose recruitment to the nucleus via GLUT4-mediated transport. ATM also activates G6PD though Hsp27, as an alternative mechanism to produce nucleotides for DNA metabolism. DNA-PK following energy depletion or metabolic rewiring promotes glycolysis through AMP signaling. This figure was created with BioRender.com.
See this image and copyright information in PMC

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