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Involvement of DNA mismatch repair in folate deficiency-induced apoptosis small star, filled
1Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky Medical Center, University of Kentucky Medical Center, 40536, Lexington, Kentucky, USA
Abstract:
Folate is a critical factor for DNA metabolism and its deficiency is associated with a number of human diseases and cancers. Although it has been shown that folate deficiency induces genomic instability and apoptotic cell death, the underlying mechanism is largely unknown. Given the role of mismatch repair in maintaining genomic integrity, mismatch repair was tested for its involvement in folate deficiency-induced genomic instability and cell death. Cells proficient in mismatch repair were highly sensitive to folate deficiency compared with cells defective in either hMutSalpha or hMutLalpha. Since wild-type cells but not mutant cells underwent apoptosis upon extensive folate depletion, the apoptotic response is dependent on a functional mismatch repair system. Our data also indicate that p53 is required for the folate depletion-induced apoptosis. In vitro biochemical studies demonstrated that hMutSalpha specifically recognized DNA damage induced by folate deficiency, suggesting a direct participation of mismatch repair proteins in mediating the apoptotic response. We conclude that while the mismatch repair-dependent apoptosis is necessary to protect damaged cells from tumorigenesis, it may damage a whole tissue or organ, as seen in patients with megaloblastic anemia, during extensive folate deficiency.
Insights
Folate deficiency causes DNA damage and cell death through the mismatch repair system. This pathway, involving p53, triggers apoptosis to prevent cancer but can harm tissues in severe deficiencies.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Folate is essential for DNA metabolism.
- Folate deficiency is linked to diseases and cancers.
- The mechanisms behind folate deficiency-induced genomic instability and cell death are unclear.
Purpose of the Study:
- To investigate the role of DNA mismatch repair (MMR) in folate deficiency-induced genomic instability and apoptosis.
- To elucidate the molecular mechanisms underlying folate deficiency-induced cell death.
Main Methods:
- Comparing the sensitivity of MMR-proficient and MMR-deficient cells to folate deficiency.
- Assessing apoptosis induction in response to folate depletion.
- Investigating the involvement of p53 in the apoptotic pathway.
- Conducting in vitro biochemical studies to examine protein-DNA interactions.
Main Results:
- MMR-proficient cells were more sensitive to folate deficiency than MMR-deficient cells.
- Apoptosis upon folate depletion was dependent on a functional MMR system and p53.
- In vitro studies showed that hMutSalpha recognizes DNA damage caused by folate deficiency.
Conclusions:
- The mismatch repair system mediates folate deficiency-induced apoptosis, a process requiring p53.
- This MMR-dependent apoptosis serves as a protective mechanism against tumorigenesis.
- Extensive folate deficiency can lead to tissue damage via this apoptotic pathway, as observed in megaloblastic anemia.
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