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Disparity between DNA base excision repair in yeast and mammals: translational implications
Mark R Kelley1, Yoke W Kow, David M Wilson
1Department of Pediatrics, Section of Hematology/Oncology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. mkelley@iupui.edu
Abstract:
One approach to the effective treatment of cancer requires the continued development of novel chemotherapeutic agents to kill tumor cells. Additionally, an element of cancer research has been devoted to understanding DNA repair pathways in hopes of defining the factors that confer resistance to anticancer drugs and developing strategies for modulating repair capacity as a means of overcoming resistance or enhancing sensitivity to cancer treatments. Historically, yeast, particularly Saccharomyces cerevisiae, has been used as a model system for DNA repair analyses. Additionally, it has been used to evaluate drug efficacy and selectivity, and to identify new targets for antitumor drugs. The usefulness of yeast for these types of analyses has been primarily because of it being considered to have well-conserved DNA repair processes among eukaryotes. However, as more information has accumulated in mammalian DNA repair, and particularly in DNA base excision repair (BER), a number of striking differences have emerged between yeast and mammalian (human) repair processes. The BER pathway is essential for the repair of damaged DNA induced by oxidizing and alkylating agents, which are the majority of chemotherapeutic drugs used currently in the clinic. The importance of this pathway in processing DNA damage makes its members potential targets for novel chemotherapeutic agents. However, because the BER process and its main players are remarkably divergent from S. cerevisiae to humans, it is worth keeping these differences in mind if yeast continues to be used as a model or primary system in the screening for potential new human therapeutics.
Insights
Yeast is a common model for studying DNA repair and anticancer drugs. However, significant differences in DNA base excision repair (BER) between yeast and humans necessitate caution when using yeast to develop new cancer therapeutics.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Cancer treatment relies on novel chemotherapeutic agents and understanding DNA repair mechanisms.
- DNA repair pathways influence resistance and sensitivity to anticancer drugs.
- Saccharomyces cerevisiae (yeast) has historically served as a model for DNA repair and drug efficacy studies due to conserved eukaryotic processes.
Purpose of the Study:
- To highlight the divergence in DNA base excision repair (BER) pathways between yeast and humans.
- To assess the implications of these differences for using yeast as a model in cancer drug development.
Main Methods:
- Comparative analysis of DNA repair pathways, focusing on base excision repair (BER).
- Review of existing literature on yeast and mammalian DNA repair mechanisms.
- Evaluation of the suitability of yeast as a model for human cancer therapeutics.
Main Results:
- Significant differences exist in BER pathways and key proteins between yeast and humans.
- These divergences impact the direct translation of findings from yeast models to human cancer treatment.
- The majority of current chemotherapeutic drugs induce DNA damage repaired by BER.
Conclusions:
- While yeast is a valuable model, its utility for screening human anticancer drugs targeting BER is limited by species-specific repair mechanisms.
- Future development of novel chemotherapeutic agents targeting BER should consider these mammalian-specific differences.
- Further research into human BER pathways is crucial for effective cancer drug discovery.