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Requirement for human Mps1/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation
Zheng-Cheng Yu1, Yi-Fu Huang2, Sheau-Yann Shieh3
1Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No 1, Sec. 1, Jen-Ai Road, Taipei 100, Taiwan Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Road, Taipei 115, Taiwan.
Abstract:
Human Mps1 (hMps1) is a protein kinase essential for mitotic checkpoints and the DNA damage response. Here, we present new evidence that hMps1 also participates in the repair of oxidative DNA lesions and cell survival through the MDM2-H2B axis. In response to oxidative stress, hMps1 phosphorylates MDM2, which in turn promotes histone H2B ubiquitination and chromatin decompaction. These events facilitate oxidative DNA damage repair and ATR-CHK1, but not ATM-CHK2 signaling. Depletion of hMps1 or MDM2 compromised H2B ubiquitination, DNA repair and cell survival. The impairment could be rescued by re-expression of WT but not the phospho-deficient MDM2 mutant, supporting the involvement of hMps1-dependent MDM2 phosphorylation in the oxidative stress response. In line with these findings, localization of RPA and base excision repair proteins to damage foci also requires MDM2 and hMps1. Significantly, like MDM2, hMps1 is upregulated in human sarcoma, suggesting high hMps1 and MDM2 expression may be beneficial for tumors constantly challenged by an oxidative micro-environment. Our study therefore identified an hMps1-MDM2-H2B signaling axis that likely plays a relevant role in tumor progression.
Insights
Human Mps1 (hMps1) protein kinase aids oxidative DNA repair and cell survival by regulating the MDM2-H2B axis. This pathway is crucial for tumor progression in oxidative environments.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Human Mps1 (hMps1) is a known protein kinase vital for mitotic checkpoints and DNA damage response.
- Oxidative stress can lead to DNA lesions, impacting cell survival and potentially contributing to tumor progression.
Purpose of the Study:
- To investigate the role of hMps1 in the repair of oxidative DNA lesions.
- To elucidate the molecular mechanisms linking hMps1 to cell survival under oxidative stress.
- To identify potential therapeutic targets in cancers with high hMps1 expression.
Main Methods:
- Investigated hMps1's role in oxidative DNA damage repair and cell survival.
- Utilized techniques to assess MDM2 phosphorylation, histone H2B ubiquitination, and chromatin decompaction.
- Examined the involvement of ATR-CHK1 and ATM-CHK2 signaling pathways.
- Depletion studies of hMps1 and MDM2 were performed.
- Assessed the impact of wild-type and mutant MDM2 re-expression.
- Analyzed the localization of DNA repair proteins to damage foci.
- Correlated hMps1 and MDM2 expression levels with human sarcoma samples.
Main Results:
- hMps1 phosphorylates MDM2, promoting histone H2B ubiquitination and chromatin decompaction, facilitating oxidative DNA repair.
- This pathway specifically enhances ATR-CHK1 signaling, not ATM-CHK2.
- Depletion of hMps1 or MDM2 impairs DNA repair and cell survival, which can be rescued by wild-type MDM2.
- hMps1 and MDM2 are required for the recruitment of repair proteins like RPA to damage sites.
- hMps1 and MDM2 are upregulated in human sarcoma.
Conclusions:
- Identified a novel hMps1-MDM2-H2B signaling axis crucial for oxidative DNA damage repair and cell survival.
- This pathway plays a significant role in tumor progression, particularly in oxidative micro-environments.
- Targeting hMps1 or MDM2 could be a potential therapeutic strategy for cancers like sarcoma.
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