Cited by 24Ubiquitin and proteasome pathwaysDNA Repair MechanismsCancer-related Molecular Pathways

Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5

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Busso, Carlos S., Wedgeworth, Courtney M., Izumi, Tadahide·2011·Nucleic Acids Research

Abstract

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.”

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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
Venue
Nucleic Acids Research
Published
2011-07-01
Volume
39
Issue
18
Pages
8017-8028
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
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
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

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