DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation.
Open accessAbstract
DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination in vivo and in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.
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USP7 regulates Pol η protein levels both positively by direct deubiquitination and negatively by stabilizing Mdm2.
“Furthermore, as Pol η is polyubiquitinated by Mdm2 (Jung et al., 2012), which is itself a substrate of USP7 (Li et al., 2004), these observations suggest that USP7 regulates Pol η protein levels both positively (by direct deubiquitination) and negatively (by stabilizing Mdm2).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Jung et al., 2012
Mdm2 associates with pol eta and targets its turnover when cells are treated with UV radiation.
“Very recently, Mdm2 was found to associate with pol eta and turnover of this polymerase was targeted by Mdm2 when cells were treated with UV radiation [53].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [53]
UV exposure leads to DNA pol eta polyubiquitination and proteasomal degradation by Mdm2.
“Additionally, UV exposure to cells led to DNA pol eta polyubiquitination and proteasomal degradation by Mdm2.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [53]
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- Authors
- Jung, Y.-S., Qian, Y., & Chen, X.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Chen, Xinbin
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 11
- Issue
- 2
- Pages
- 177-184
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC3260346
- OpenAlex
- W2132603942
- Cited by
- 57
- References
- 26
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 7 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 6
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA121137, R01CA123227, CA123227, P30CA093373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- DNA polymerase eta, MDM2, polyubiquitination, proteasomal degradation, UV irradiation, xeroderma pigmentosum variant, Y-family DNA polymerases, translesion synthesis, E3 ubiquitin ligase, p53, UV-induced DNA damage, skin cancer prevention, protein stability
- MeSH terms
- Y-Family DNA Polymerases, Cell Line, Cell Survival, DNA-Directed DNA Polymerase, Humans, Protein Binding, Ultraviolet Rays, Cell Death, Polyubiquitin, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Ubiquitination, Gene Knockdown Techniques, Proteolysis
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