Distinct APE1 Activities Affect the Regulation of VEGF Transcription Under Hypoxic Conditions
| Autor: | Dong Wang, Mengxia Li, Zhaoyang Zhong, Nan Dai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
DNA damage
DNA polymerase DNA repair APE1 Apurinic/apyrimidinic endonuclease lcsh:Biotechnology VEGF Vascular endothelial growth factor OGG1 DNA Oxoguanine glycosylase 1 Biophysics Egr-1 Early growth response protein-1 HUVEC Human umbilical vein endothelial cells Biochemistry Pol β DNA Polymerase β AP endonuclease Redox 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Structural Biology Transcription (biology) HRE Hypoxic response element lcsh:TP248.13-248.65 AP sites Apurinic/apyrimidinic sites EMSA Electrophoretic mobility-shift assay Genetics AP site Hypoxia qPCR Quantitative PCR 030304 developmental biology 0303 health sciences biology Co-IP Coimmunoprecipitation HIF-1 NF-κB Nuclear factor-kappa B Promoter HIF-1 Hypoxia-induced factor-1 Fapy Formamidopyrimidine Computer Science Applications Cell biology Vascular endothelial growth factor chemistry APE1 030220 oncology & carcinogenesis BER Base excision repair biology.protein Research Article Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 17, Iss, Pp 324-332 (2019) Computational and Structural Biotechnology Journal |
| ISSN: | 2001-0370 |
| DOI: | 10.1016/j.csbj.2019.02.007 |
| Popis: | Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF), a crucial factor in tumor angiogenesis, has been reported to be transcriptionally regulated by hypoxia-inducible factor-1 (HIF-1). An 8-oxo-G or apurinic/apyrimidinic (AP) site, which is frequently associated with DNA damage, has been identified in the promoter region of VEGF. However, the detailed molecular mechanisms by which AP sites regulate VEGF gene transcription are largely unknown. The dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) is both the key enzyme in DNA base excision repair and the redox factor shown to regulate HIF-1 DNA-binding activity. In the present study, we tested the involvement of both the AP endonuclease and redox activity of APE1 in regulating HIF-1 DNA binding and VEGF transcription in HUVECs. By employing two APE1 activity-specific inhibitors and AP-site-containing reporter constructs, we confirmed that both activities of APE1 were involved in regulating VEGF expression under hypoxic conditions. Furthermore, we found that the interaction between APE1 and its downstream repair enzyme, DNA polymerase β, was compromised when the N-terminal structure of APE1 was distorted under oxidative conditions. Our data suggest that the DNA repair and redox activity of APE1 can play a collaborative role in regulating the transcriptional initiation of the AP-site-containing promoter. Keywords: Hypoxia, HIF-1, APE1, Redox, AP site |
| Databáze: | OpenAIRE |
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