Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5
Open accessAbstract
Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. We here report that ubiquitination of T233E APE1, a mimicry of phospho-T233 APE1, was markedly increased in multiple cell lines. Expression of CDK5 enhanced monoubiquitination of endogenous APE1. Polyubiquitinated APE1 was decreased when K48R ubiquitin was expressed, suggesting that polyubiquitination was mediated mainly through Lys48 of ubiquitin. The ubiquitination activity of MDM2, consistent in its role for APE1 ubiquitination, was increased for T233E APE1 compared to the wild-type APE1. In mouse embryonic fibroblasts lacking the MDM2 gene, ubiquitination of T233E APE1 was still observed probably because of the decreased degradation activity for monoubiquitinated APE1 and because of backup E3 ligases in the cells. Monoubiquitinated APE1 was present in the nucleus, and analyzing global gene expression profiles with or without induction of a ubiquitin-APE1 fusion gene suggested that monoubiquitination enhanced the gene suppression activity of APE1. These data reveal a delicate balance of ubiquitination and phosphorylation activities that alter the gene regulatory function of APE1.
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Ape1 ubiquitination at specific sites is at least partially dependent on Mdm2-mediated E3 ubiquitin ligase activity, but Ape1 ubiquitination is also controlled by additional ligases.
“These sites were at least partially dependent on Mdm2-mediated E3 ubiquitin ligase activity, but the authors acknowledged that Ape1 ubiquitination is controlled by additional ligases.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [17]
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- Authors
- Busso, C. S., Wedgeworth, C. M., & Izumi, T.
- Affiliations
- Louisiana State University Health Sciences Center New Orleans (US)
- Corresponding author
- Izumi, Tadahide
- ORCID
- Izumi, Tadahide
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-07-01
- Volume
- 39
- Issue
- 18
- Pages
- 8017-8028
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3185409
- OpenAlex
- W2074947103
- Cited by
- 24
- References
- 63
- Citations by year
- 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA98664)
- 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, apurinic/apyrimidinic endonuclease 1, ubiquitination, cyclin-dependent kinase 5, MDM2, K48-linked polyubiquitination, protein degradation, DNA repair, global gene expression
- MeSH terms
- Animals, Cell Line, Humans, Lysine, Threonine, Glutamic Acid, Amino Acid Substitution, DNA-(Apurinic or Apyrimidinic Site) Lyase, Cell Line, Tumor, Cyclin-Dependent Kinase 5, Mice, Proto-Oncogene Proteins c-mdm2, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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