Regulation of PDGFR-ß gene expression by targeting the G-vacancy bearing G-quadruplex in promoter.
Nucleic Acids Res
; 49(22): 12634-12643, 2021 12 16.
Article
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| MEDLINE
| ID: mdl-34850916
ABSTRACT
G-quadruplex is an essential element in gene transcription that serves as a promising drug target. Guanine-vacancy-bearing G-quadruplex (GVBQ) is a newly identified G-quadruplex that has distinct structural features from the canonical G-quadruplex. Potential GVBQ-forming motifs are widely distributed in gene promoter regions. However, whether GVBQ can form in genomic DNA and be an effective target for manipulating gene expression is unknown. Using photo-crosslinking, dimethyl sulfate footprinting, exonuclease digestion and in vitro transcription, we demonstrated the formation of a GVBQ in the G-rich nuclease hypersensitivity element within the human PDGFR-ß gene promoter region in both single-stranded and double-stranded DNA. The formation of GVBQ in dsDNA could be induced by negative supercoiling created by downstream transcription. We also found that the PDGFR-ß GVBQ was specifically recognized and stabilized by a new synthetic porphyrin guanine conjugate (mPG). Targeting the PDGFR-ß GVBQ in human cancer cells using the mPG could specifically alter PDGFR-ß gene expression. Our work illustrates that targeting GVBQ with mPG in human cells can regulate the expression level of a specific gene, thus indicating a novel strategy for drug development.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación de la Expresión Génica
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Regiones Promotoras Genéticas
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Receptor beta de Factor de Crecimiento Derivado de Plaquetas
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G-Cuádruplex
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2021
Tipo del documento:
Article