G-Quadruplex loops regulate PARP-1 enzymatic activation
| Autor: | John C. Marecki, Alicia K. Byrd, Andrea D Edwards, Kevin D. Raney, Jun Gao |
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| Rok vydání: | 2020 |
| Předmět: |
Guanine
AcademicSubjects/SCI00010 DNA repair DNA damage Poly ADP ribose polymerase Poly (ADP-Ribose) Polymerase-1 Biology 010402 general chemistry Proto-Oncogene Mas 01 natural sciences Catalysis Chromatin remodeling Substrate Specificity Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Transcription (biology) Genetics Humans heterocyclic compounds Promoter Regions Genetic 030304 developmental biology 0303 health sciences Nucleic Acid Enzymes Promoter Recombinant Proteins 0104 chemical sciences Cell biology Enzyme Activation G-Quadruplexes Proto-Oncogene Proteins c-kit chemistry Regulatory sequence Oxidation-Reduction DNA DNA Damage |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | G-Quadruplexes are non-B form DNA structures present at regulatory regions in the genome, such as promoters of proto-oncogenes and telomeres. The prominence in such sites suggests G-quadruplexes serve an important regulatory role in the cell. Indeed, oxidized G-quadruplexes found at regulatory sites are regarded as epigenetic elements and are associated with an interlinking of DNA repair and transcription. PARP-1 binds damaged DNA and non-B form DNA, where it covalently modifies repair enzymes or chromatin-associated proteins respectively with poly(ADP-ribose) (PAR). PAR serves as a signal in regulation of transcription, chromatin remodeling, and DNA repair. PARP-1 is known to bind G-quadruplexes with stimulation of enzymatic activity. We show that PARP-1 binds several G-quadruplex structures with nanomolar affinities, but only a subset promote PARP-1 activity. The G-quadruplex forming sequence found in the proto-oncogene c-KIT promoter stimulates enzymatic activity of PARP-1. The loop-forming characteristics of the c-KIT G-quadruplex sequence regulate PARP-1 catalytic activity, whereas eliminating these loop features reduces PARP-1 activity. Oxidized G-quadruplexes that have been suggested to form unique, looped structures stimulate PARP-1 activity. Our results support a functional interaction between PARP-1 and G-quadruplexes. PARP-1 enzymatic activation by G-quadruplexes is dependent on the loop features and the presence of oxidative damage. |
| Databáze: | OpenAIRE |
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