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Updated: Jul 5, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Role of mismatch repair and MGMT in response to anticancer therapies
Ida Casorelli1, Maria Teresa Russo, Margherita Bignami
1Section of Experimental Carcinogenesis, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
Abstract:
Tumor resistance to cytotoxic chemotherapy drugs and their toxicity to normal cells are major clinical obstacles to anticancer therapy effectiveness. Alterations in various DNA repair pathways play a key role in the development of both mechanisms of drug resistance and toxicity. Since deregulation of the DNA damage response and alterations in DNA repair pathways are relatively common in human cancer, the knowledge of these alterations in cancer cells would be an important predictive factor for the clinical response to chemotherapy and a useful guide in designing an appropriate therapeutic strategy. This review is focused on the mismatch repair (MMR) pathway and the O(6)-methylguanine-DNA-methyltransferase (MGMT) repair protein. In particular, we examine how inactivation of these DNA repair mechanisms might affect the response of tumor cells to chemotherapy, with a special emphasis on agents inducing methylation and oxidative DNA damage and interstrand DNA cross-links (ICLs). In addition, we provide novel experimental evidence indicating that MMR is required for efficient repair of ICLs via stabilization of RAD51 containing repair intermediates. Finally, we discuss possible emerging therapeutical strategies for treating MMR-defective tumors.
Insights
DNA repair pathways like mismatch repair (MMR) and MGMT are crucial for chemotherapy effectiveness. Understanding their role in drug resistance and toxicity can guide better anticancer therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumor resistance to chemotherapy and normal cell toxicity are major clinical challenges.
- DNA repair pathway alterations are key contributors to both drug resistance and toxicity.
- Understanding these alterations can predict chemotherapy response and guide therapeutic strategies.
Purpose of the Study:
- To review the role of DNA repair pathways, specifically mismatch repair (MMR) and O(6)-methylguanine-DNA-methyltransferase (MGMT), in anticancer therapy.
- To examine how inactivating these repair mechanisms affects tumor cell response to chemotherapy, focusing on methylation, oxidative damage, and interstrand cross-links (ICLs).
- To present new evidence on MMR's role in ICL repair and discuss therapeutic strategies for MMR-defective tumors.
Main Methods:
- Literature review of DNA repair pathways (MMR and MGMT) in cancer therapy.
- Analysis of how DNA repair alterations influence chemotherapy response and toxicity.
- Experimental investigation of MMR's role in repairing interstrand DNA cross-links (ICLs).
Main Results:
- Inactivation of MMR and MGMT pathways can significantly impact tumor cell sensitivity to chemotherapy.
- MMR is essential for the efficient repair of ICLs, likely through stabilizing RAD51-containing repair intermediates.
- Novel experimental data support MMR's critical function in DNA repair.
Conclusions:
- Targeting DNA repair pathways, particularly MMR, offers potential therapeutic strategies for MMR-defective tumors.
- Understanding the interplay between DNA repair mechanisms and chemotherapy is vital for optimizing cancer treatment.
- Further research into MMR-defective tumor therapies is warranted.
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