Msh2 deficiency does not contribute to cisplatin resistance in mouse embryonic stem cells
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Updated: Aug 29, 2026
An Alternative Culture Method to Maintain Genomic Hypomethylation of Mouse Embryonic Stem Cells Using MEK Inhibitor PD0325901 and Vitamin C
Published on: June 1, 2018
1Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Abstract:
Several reports have suggested that a defect in the DNA mismatch repair (MMR) system not only causes resistance to methylating agents but also confers low-level resistance to the chemotherapeutic drug cisplatin. Here we report that in a clonogenic assay, mouse embryonic stem (ES) cells deficient for the MMR protein MSH2 respond similarly as wild-type cells to cisplatin. Furthermore, restoring MSH2 expression in a cisplatin-resistant subclone selected from an Msh2(-/-) cell population did not sensitize cells to cisplatin. To ascertain that our observations were not the result of a mutation in the Msh2(-/-) cells that obscured the contribution of a defective MMR machinery to cisplatin resistance, we made use of the Cre-lox system to create a cell line in which the Msh2 gene can be conditionally inactivated. However, while de novo inactivation of Msh2 rendered cells tolerant to the methylating drug N-methyl-N'-nitro-N-nitrosoguanidine as expected, it did not alter the sensitivity to cisplatin. In addition, we were not able to derive cisplatin-resistant subclones from this freshly generated MMR-deficient cell line. Thus, in ES cells we did not find evidence for direct involvement of MMR deficiency in cisplatin resistance.
Insights
DNA mismatch repair (MMR) deficiency does not impact cisplatin resistance in mouse embryonic stem cells. Studies show MSH2-deficient cells exhibit similar sensitivity to cisplatin, challenging previous findings on MMR defects and chemotherapy response.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The DNA mismatch repair (MMR) system corrects errors during DNA replication.
- Previous studies suggested MMR defects confer resistance to methylating agents and cisplatin.
- The role of MMR deficiency in cisplatin resistance requires further investigation.
Purpose of the Study:
- To investigate the direct involvement of MMR deficiency, specifically MSH2, in cisplatin resistance.
- To determine if MSH2 deficiency affects cisplatin sensitivity in mouse embryonic stem (ES) cells.
Main Methods:
- Clonogenic assays were used to assess cisplatin sensitivity in MSH2-deficient and wild-type mouse ES cells.
- MSH2 expression was restored in resistant subclones to evaluate its effect on sensitivity.
- The Cre-lox system was employed to conditionally inactivate the Msh2 gene.
- Sensitivity to cisplatin and N-methyl-N'-nitro-N-nitrosoguanidine was tested in MMR-deficient cells.
Main Results:
- Mouse ES cells deficient for MSH2 showed similar sensitivity to cisplatin as wild-type cells.
- Restoring MSH2 expression did not re-sensitize cisplatin-resistant cells.
- Conditional inactivation of Msh2 conferred tolerance to a methylating agent but not altered cisplatin sensitivity.
- No cisplatin-resistant subclones were derived from newly generated MMR-deficient cells.
Conclusions:
- MMR deficiency, specifically MSH2, does not directly contribute to cisplatin resistance in mouse ES cells.
- These findings contradict previous reports suggesting a link between MMR defects and cisplatin resistance.
- The study highlights the complexity of DNA repair pathways in response to chemotherapy.
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