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Published on: August 21, 2021
Role of DNA mismatch repair in apoptotic responses to therapeutic agents
Mark Meyers1, Arlene Hwang, Mark W Wagner
1Department of Radiation Oncology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Abstract:
Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and 5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro-2'-deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.
Insights
DNA mismatch repair (MMR) deficiency impacts cancer treatment response. This study shows MMR status does not enhance apoptosis in cells treated with 5-fluoro-2'-deoxyuridine, suggesting apoptosis is a minor part of cell death.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- DNA mismatch repair (MMR) is crucial for correcting DNA replication errors and suppressing recombination.
- MMR deficiency is implicated in hereditary nonpolyposis colorectal cancer and sporadic cancers.
- MMR status influences cellular responses to various chemotherapeutic agents and radiation.
Purpose of the Study:
- To review the mechanisms of MMR and apoptosis.
- To investigate the impact of MMR status on apoptosis following therapeutic agent treatment.
- To experimentally assess apoptosis induction in MMR-deficient versus MMR-proficient cells.
Main Methods:
- Literature review on MMR, apoptosis, and therapeutic agent response.
- Experimental use of isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cell lines.
- Treatment of cells with 5-fluoro-2 extquotesingle-deoxyuridine to assess apoptosis.
Main Results:
- MMR status influences cellular response to DNA-damaging agents.
- No enhanced apoptosis was observed in MMR-proficient cells compared to MMR-deficient cells after 5-fluoro-2 extquotesingle-deoxyuridine treatment.
- Apoptosis constitutes a small fraction of the overall cell death induced by 5-fluoro-2 extquotesingle-deoxyuridine.
Conclusions:
- MMR deficiency is a significant factor in cancer development and treatment response.
- The study's findings suggest that MMR status may not directly enhance apoptosis induction by certain chemotherapeutics.
- Apoptosis is a limited component of the cell death pathway triggered by 5-fluoro-2 extquotesingle-deoxyuridine, irrespective of MMR status.
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