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Updated: Jul 10, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Evidence that dysregulated DNA mismatch repair characterizes human nonmelanoma skin cancer
L C Young1, J Listgarten, M J Trotter
1Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Background:
In addition to an established role in the repair of postreplicative DNA errors, DNA mismatch repair (MMR) proteins also contribute to cellular responses to exogenous DNA damage. Previously, we have shown that Msh2-null mice display increased sensitivity to ultraviolet (UV) B-induced tumorigenesis, but squamous cell carcinomas (SCC) generated are microsatellite stable, suggesting a role for MMR other than postreplicative repair in UV-induced cutaneous tumour formation.
Objectives:
We questioned whether there was evidence of MMR dysfunction in human SCC, thus validating the mouse models of MMR-dependent UVB-induced skin cancer.
Methods:
Using tissue microarrays we examined both nuclear and cytoplasmic levels of MMR proteins MSH2, MSH6, MSH3, MLH1 and PMS2 in more than 200 cases of cutaneous SCC and basal cell carcinoma (BCC).
Results:
We found that subsets of these 10 MMR protein measures were increased in nonmelanoma skin cancer (NMSC) compared with normal epidermal samples; this was particularly true of SCC. In fact, based on post hoc tests and MMR protein distribution patterns, BCC was distinct from SCC. With the exception of nuclear MSH2, the BCC had lower levels of identified MMR protein measures than SCC. We believe this to be important because not only is SCC more aggressive than BCC, but evidence suggests that these two NMSC subtypes arise through different molecular pathways.
Conclusions:
In combination with previously established roles for MMR proteins in response to UVB-induced DNA damage, our data point towards an expanded perspective of the importance of MMR proteins in the suppression of UVB-induced tumorigenesis and, potentially, tumour behaviour.
Insights
DNA mismatch repair (MMR) proteins are crucial for repairing DNA damage from UV radiation. This study found altered MMR protein levels in human skin cancers, supporting their role in UV-induced tumor suppression.
Area of Science:
- Molecular biology
- Dermatology
- Cancer research
Background:
- DNA mismatch repair (MMR) proteins are known for correcting DNA replication errors.
- MMR proteins also play a role in cellular responses to external DNA damage, including UV radiation.
- Previous studies showed Msh2-null mice are sensitive to UVB-induced tumors, but these tumors were microsatellite stable, suggesting MMR's role beyond replication repair.
Purpose of the Study:
- To investigate if DNA mismatch repair (MMR) dysfunction is present in human squamous cell carcinoma (SCC).
- To validate mouse models of MMR-dependent UVB-induced skin cancer by examining human SCC.
- To compare MMR protein levels in different non-melanoma skin cancer subtypes.
Main Methods:
- Tissue microarrays were used to analyze MMR protein levels.
- Nuclear and cytoplasmic levels of MSH2, MSH6, MSH3, MLH1, and PMS2 were quantified.
- Over 200 cases of cutaneous SCC and basal cell carcinoma (BCC) were analyzed, alongside normal epidermal samples.
Main Results:
- Subsets of MMR protein measures were elevated in non-melanoma skin cancer (NMSC), particularly SCC, compared to normal skin.
- Basal cell carcinoma (BCC) showed distinct MMR protein distribution patterns compared to SCC.
- BCC generally had lower levels of most MMR proteins than SCC, with the exception of nuclear MSH2.
Conclusions:
- The findings suggest an expanded role for MMR proteins in suppressing UVB-induced skin tumorigenesis.
- Altered MMR protein levels in human skin cancers support their involvement in UV-induced tumor development and behavior.
- MMR proteins are important in cellular responses to DNA damage, influencing skin cancer progression.
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