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The DNA Structure-Specific Endonuclease MUS81 Mediates DNA Sensor STING-Dependent Host Rejection of Prostate Cancer
Samantha S W Ho1, Wendy Y L Zhang1, Nikki Yi Jie Tan1
1Immunology Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
Abstract:
Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.
Insights
The tumor suppressor MUS81 enzyme and DNA repair pathways cause self-DNA to accumulate in prostate cancer cells, triggering immune responses against tumors. This discovery reveals how cancer cells alert the immune system to their presence.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Self-DNA in the cytosol of cancer cells can trigger anti-tumor immunity, but its origins are unclear.
- Understanding cytosolic DNA mechanisms is crucial for cancer immunotherapy.
- Prostate cancer cells harbor cytosolic DNA, suggesting a role in immune surveillance.
Purpose of the Study:
- To elucidate the mechanisms behind cytosolic DNA accumulation in prostate cancer cells.
- To investigate the role of the endonuclease MUS81 and DNA repair pathways in cytosolic DNA generation.
- To determine how cytosolic DNA influences the anti-tumor immune response.
Main Methods:
- Analyzing MUS81 foci and cytosolic double-stranded DNA (dsDNA) levels in prostate cancer tissues across different stages.
- Investigating the link between MUS81 activity, PARP-dependent DNA repair, and cytosolic DNA.
- Assessing the impact of MUS81-generated cytosolic DNA on STING-dependent type I interferon (IFN) production.
- Evaluating the role of macrophages and T cells in IFN-mediated tumor cell rejection.
Main Results:
- MUS81 cleavage and PARP-dependent DNA repair pathways lead to cytosolic DNA accumulation in prostate cancer.
- Increased MUS81 foci and cytosolic dsDNA correlate with early-stage prostate cancer (hyperplasia to stage II) and decrease in stage III.
- Cytosolic DNA activates STING-dependent type I IFN signaling, enhancing phagocytic and T cell responses.
- IFN-mediated tumor cell rejection involves macrophages and T cells, highlighting an immune alert system.
Conclusions:
- MUS81 acts as a tumor suppressor by generating cytosolic DNA that alerts the immune system to transformed cells.
- The MUS81-PARP pathway is a key source of immunogenic cytosolic DNA in prostate cancer.
- This mechanism links DNA damage and repair to innate and adaptive anti-tumor immunity.
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