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Published on: March 31, 2022
Modelling DNA Repair Pathways: Recent Advances and Future Directions
Francesco Gentile, Jack A Tuszynski, Khaled H Barakat1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. kbarakat@ualberta.ca.
Background:
A major class of chemotherapy drugs targets the genome of cancer cells. These DNA damaging agents induce damage to the DNA helix, resulting in the programmed death of cancer cells. An overactivated DNA repair mechanism in cancer cells can reduce the efficacy of these drugs, thereby eliminating their therapeutic benefit and developing an acquired resistance to these otherwise effective drugs. A promising approach to enhance the therapeutic window of DNA damaging agents is to target the DNA repair pathways causing this type of resistance.
Methods:
Computational approaches have been applied successfully to study many of these DNA repair mechanisms at different scales and focusing on various aspects. The ultimate goal of these studies has been to identify the key players in developing resistance to DNA damaging agents and to design regulators for their activities. This review covers the most important and recent computational efforts toward this goal. This includes modelling the mechanisms involved in DNA repair and identifying novel pharmacological inhibitors for their activities.
Results:
We focus here mainly on the pathways associated with an acquired drug resistance to DNA damaging agents, concentrating on the recent advances in modelling the key mechanisms and foreseeing the future directions in this field.
Conclusion:
We hope that this short, yet comprehensive review can help in discovering novel strategies to overcome the resistance effects inherent in various cancer treatments.
Insights
Targeting DNA repair mechanisms can overcome cancer drug resistance. Computational modeling aids in identifying key resistance players and designing new drugs to improve chemotherapy effectiveness.
Area of Science:
- Oncology
- Computational Biology
- Pharmacology
Background:
- Chemotherapy drugs target cancer cell genomes, inducing DNA damage for programmed cell death.
- Overactivated DNA repair mechanisms in cancer cells confer resistance to DNA damaging agents, reducing therapeutic efficacy.
- Targeting DNA repair pathways is a promising strategy to enhance the therapeutic window of chemotherapy.
Purpose of the Study:
- To review computational approaches for studying DNA repair mechanisms.
- To identify key players in acquired resistance to DNA damaging agents.
- To explore novel pharmacological inhibitors for DNA repair pathways.
Main Methods:
- Computational modeling of DNA repair mechanisms at various scales.
- Analysis of recent computational efforts in understanding drug resistance.
- Focus on pathways associated with acquired resistance to DNA damaging agents.
Main Results:
- Computational approaches have successfully identified key players in resistance.
- Modeling of DNA repair mechanisms provides insights into resistance pathways.
- Identification of potential targets for novel pharmacological inhibitors.
Conclusions:
- Computational strategies are crucial for understanding and overcoming cancer drug resistance.
- This review highlights recent advances in modeling DNA repair and resistance.
- Future directions involve developing novel strategies to combat resistance in cancer treatment.
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