Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway
Open accessAbstract
APE1/Ref-1 is an essential DNA repair/gene regulatory protein in mammals of which intracellular level significantly affects cellular sensitivity to genotoxicants. The apurinic/apyrimidinic endonuclease 1 (APE1) functions are altered by phosphorylation and acetylation. We here report that APE1 is also modified by ubiquitination. APE1 ubiquitination occurred specifically at Lys residues near the N-terminus, and was markedly enhanced by mouse double minute 2 (MDM2), the major intracellular p53 inhibitor. Moreover, DNA-damaging reagents and nutlin-3, an inhibitor of MDM2-p53 interaction, increased APE1 ubiquitination in the presence of p53. Downmodulation of MDM2 increased APE1 level, suggesting that MDM2-mediated ubiquitination can be a signal for APE1 degradation. In addition, unlike the wild-type APE1, ubiquitin-APE1 fusion proteins were predominantly present in the cytoplasm. Therefore, monoubiquitination not only is a prerequisite for degradation, but may also alter the APE1 activities in cells. These results reveal a novel regulation of APE1 through ubiquitination.
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Ape1 is polyubiquitinated in HCT116 cells after H2O2 treatment, and purified Ape1 mixed with HeLa cell extracts forms a distinct monoubiquitination pattern.
“Ape1 was found to be polyubiquitinated in a human cancer cell line, HCT116, after H2O2 treatment and purified Ape1 protein mixed with HeLa cell extracts formed a distinct monoubiquitination pattern [16].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [16]
Mdm2 leads to Ape1 monoubiquitination, whereas the RING-finger Mdm2 mutant C464S does not.
“Examination of the E3 ligase Mdm2 showed that Mdm2 led to Ape1 monoubiquitination, while the RING-finger Mdm2 mutant (C464S) did not.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [16]
Mdm2 and Ape1 interact under conditions of overexpression, but not as endogenous proteins.
“Mdm2 and Ape1 were demonstrated to interact together under conditions of overexpression, yet not endogenous proteins.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [16]
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References 58 · Cited by 100
- Authors
- Busso, C. S., Iwakuma, T., & Izumi, T.
- Affiliations
- Louisiana State University Health Sciences Center New Orleans (US)
- Corresponding author
- Izumi, T
- ORCID
- Venue
- Oncogene
- Published
- 2009-02-16
- Volume
- 28
- Issue
- 13
- Pages
- 1616-1625
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2664849
- OpenAlex
- W2020781844
- Cited by
- 100
- References
- 58
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 11 · 2015: 5 · 2014: 9 · 2013: 14 · 2012: 11
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA98664, R56CA098664, R01CA098664)
- 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
- APE1, Ref-1, ubiquitination, p53, MDM2, DNA repair, monoubiquitination, protein degradation, Nutlin-3, DNA damage response, lysine modification, cytoplasmic localization
- MeSH terms
- Animals, Cells, Cultured, DNA Repair, Humans, Mammals, Signal Transduction, Tumor Suppressor Protein p53, NIH 3T3 Cells, DNA-(Apurinic or Apyrimidinic Site) Lyase, HCT116 Cells, Mice, Proto-Oncogene Proteins c-mdm2, Ubiquitination
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