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Updated: Nov 11, 2025
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer
Matteo Lulli1, Laura Del Coco2, Tommaso Mello3
1Department of Experimental and Clinical Biomedical Sciences "Mario Serio", General Pathology Unit, University of Florence, Florence, Italy.
Abstract:
Defective mitosis with chromosome missegregation can have a dramatic effect on genome integrity by causing DNA damage, activation of the DNA damage response (DDR), and chromosomal instability. Although this is an energy-dependent process, mechanisms linking DDR to cellular metabolism are unknown. Here we show that checkpoint kinase 2 (CHK2), a central effector of DDR, regulates cellular energy production by affecting glycolysis and mitochondrial functions. Patients with hepatocellular carcinoma (HCC) had increased CHK2 mRNA in blood, which was associated with elevated tricarboxylic acid cycle (TCA) metabolites. CHK2 controlled expression of succinate dehydrogenase (SDH) and intervened with mitochondrial functions. DNA damage and CHK2 promoted SDH activity marked by increased succinate oxidation through the TCA cycle; this was confirmed in a transgenic model of HCC with elevated DNA damage. Mitochondrial analysis identified CHK2-controlled expression of SDH as key in sustaining reactive oxygen species production. Cells with DNA damage and elevated CHK2 relied significantly on glycolysis for ATP production due to dysfunctional mitochondria, which was abolished by CHK2 knockdown. This represents a vulnerability created by the DNA damage response that could be exploited for development of new therapies. SIGNIFICANCE: This study uncovers a link between a central effector of DNA damage response, CHK2, and cellular metabolism, revealing potential therapeutic strategies for targeting hepatocellular carcinoma.
Insights
DNA damage response protein CHK2 regulates cellular energy by impacting glycolysis and mitochondria. This discovery offers new therapeutic strategies for targeting hepatocellular carcinoma (HCC) by exploiting metabolic vulnerabilities.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Defective mitosis and chromosome missegregation lead to DNA damage and genomic instability.
- The link between DNA damage response (DDR) and cellular metabolism remains largely unknown.
- Energy production is crucial for DNA damage response pathways.
Purpose of the Study:
- To investigate the role of checkpoint kinase 2 (CHK2) in linking DNA damage response to cellular metabolism.
- To explore potential therapeutic targets in hepatocellular carcinoma (HCC) based on metabolic alterations.
Main Methods:
- Analysis of CHK2 mRNA levels in HCC patients' blood.
- Assessing glycolysis and mitochondrial function in response to DNA damage and CHK2 activity.
- Investigating the effect of CHK2 on succinate dehydrogenase (SDH) expression and activity.
- Utilizing a transgenic HCC model with elevated DNA damage.
Main Results:
- Increased CHK2 mRNA in HCC patients correlated with elevated tricarboxylic acid cycle (TCA) metabolites.
- CHK2 regulates SDH expression and mitochondrial function, promoting succinate oxidation.
- DNA damage and CHK2 activation sustain reactive oxygen species production.
- Cells with DNA damage and high CHK2 rely on glycolysis due to mitochondrial dysfunction, a vulnerability exploitable by CHK2 knockdown.
Conclusions:
- Checkpoint kinase 2 (CHK2) acts as a crucial link between DNA damage response and cellular metabolism.
- CHK2 influences glycolysis and mitochondrial function, impacting energy production.
- Targeting CHK2-mediated metabolic alterations presents a potential therapeutic strategy for hepatocellular carcinoma (HCC).
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