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G-Quadruplex loops regulate PARP-1 enzymatic activation

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...

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Autores principales: Edwards, Andrea D, Marecki, John C, Byrd, Alicia K, Gao, Jun, Raney, Kevin D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797039/
https://www.ncbi.nlm.nih.gov/pubmed/33313902
http://dx.doi.org/10.1093/nar/gkaa1172
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author Edwards, Andrea D
Marecki, John C
Byrd, Alicia K
Gao, Jun
Raney, Kevin D
author_facet Edwards, Andrea D
Marecki, John C
Byrd, Alicia K
Gao, Jun
Raney, Kevin D
author_sort Edwards, Andrea D
collection PubMed
description 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.
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spelling pubmed-77970392021-01-13 G-Quadruplex loops regulate PARP-1 enzymatic activation Edwards, Andrea D Marecki, John C Byrd, Alicia K Gao, Jun Raney, Kevin D Nucleic Acids Res Nucleic Acid Enzymes 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. Oxford University Press 2020-12-11 /pmc/articles/PMC7797039/ /pubmed/33313902 http://dx.doi.org/10.1093/nar/gkaa1172 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Nucleic Acid Enzymes
Edwards, Andrea D
Marecki, John C
Byrd, Alicia K
Gao, Jun
Raney, Kevin D
G-Quadruplex loops regulate PARP-1 enzymatic activation
title G-Quadruplex loops regulate PARP-1 enzymatic activation
title_full G-Quadruplex loops regulate PARP-1 enzymatic activation
title_fullStr G-Quadruplex loops regulate PARP-1 enzymatic activation
title_full_unstemmed G-Quadruplex loops regulate PARP-1 enzymatic activation
title_short G-Quadruplex loops regulate PARP-1 enzymatic activation
title_sort g-quadruplex loops regulate parp-1 enzymatic activation
topic Nucleic Acid Enzymes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797039/
https://www.ncbi.nlm.nih.gov/pubmed/33313902
http://dx.doi.org/10.1093/nar/gkaa1172
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