Cargando…

Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation

We have investigated the function of human topoisomerase 1 (TOP1) in regulation of G-quadruplex (G4) formation in the Pu27 region of the MYC P1 promoter. Pu27 is among the best characterized G4 forming sequences in the human genome and it is well known that promoter activity is inhibited upon G4 for...

Descripción completa

Detalles Bibliográficos
Autores principales: Keller, Josephine Geertsen, Hymøller, Kirstine Mejlstrup, Thorsager, Maria Eriksen, Hansen, Noriko Y, Erlandsen, Jens Uldum, Tesauro, Cinzia, Simonsen, Anne Katrine W, Andersen, Anne Bech, Vandsø Petersen, Kamilla, Holm, Lise Lolle, Stougaard, Magnus, Andresen, Brage Storstein, Kristensen, Peter, Frøhlich, Rikke, Knudsen, Birgitta R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226537/
https://www.ncbi.nlm.nih.gov/pubmed/35687110
http://dx.doi.org/10.1093/nar/gkac482
_version_ 1784733922962178048
author Keller, Josephine Geertsen
Hymøller, Kirstine Mejlstrup
Thorsager, Maria Eriksen
Hansen, Noriko Y
Erlandsen, Jens Uldum
Tesauro, Cinzia
Simonsen, Anne Katrine W
Andersen, Anne Bech
Vandsø Petersen, Kamilla
Holm, Lise Lolle
Stougaard, Magnus
Andresen, Brage Storstein
Kristensen, Peter
Frøhlich, Rikke
Knudsen, Birgitta R
author_facet Keller, Josephine Geertsen
Hymøller, Kirstine Mejlstrup
Thorsager, Maria Eriksen
Hansen, Noriko Y
Erlandsen, Jens Uldum
Tesauro, Cinzia
Simonsen, Anne Katrine W
Andersen, Anne Bech
Vandsø Petersen, Kamilla
Holm, Lise Lolle
Stougaard, Magnus
Andresen, Brage Storstein
Kristensen, Peter
Frøhlich, Rikke
Knudsen, Birgitta R
author_sort Keller, Josephine Geertsen
collection PubMed
description We have investigated the function of human topoisomerase 1 (TOP1) in regulation of G-quadruplex (G4) formation in the Pu27 region of the MYC P1 promoter. Pu27 is among the best characterized G4 forming sequences in the human genome and it is well known that promoter activity is inhibited upon G4 formation in this region. We found that TOP1 downregulation stimulated transcription from a promoter with wildtype Pu27 but not if the G4 motif in Pu27 was interrupted by mutation(s). The effect was not specific to the MYC promoter and similar results were obtained for the G4 forming promoter element WT21. The other major DNA topoisomerases with relaxation activity, topoisomerases 2α and β, on the other hand, did not affect G4 dependent promoter activity. The cellular studies were supported by in vitro investigations demonstrating a high affinity of TOP1 for wildtype Pu27 but not for mutant sequences unable to form G4. Moreover, TOP1 was able to induce G4 formation in Pu27 inserted in double stranded plasmid DNA in vitro. This is the first time TOP1 has been demonstrated capable of inducing G4 formation in double stranded DNA and of influencing G4 formation in cells.
format Online
Article
Text
id pubmed-9226537
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-92265372022-06-28 Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation Keller, Josephine Geertsen Hymøller, Kirstine Mejlstrup Thorsager, Maria Eriksen Hansen, Noriko Y Erlandsen, Jens Uldum Tesauro, Cinzia Simonsen, Anne Katrine W Andersen, Anne Bech Vandsø Petersen, Kamilla Holm, Lise Lolle Stougaard, Magnus Andresen, Brage Storstein Kristensen, Peter Frøhlich, Rikke Knudsen, Birgitta R Nucleic Acids Res Molecular Biology We have investigated the function of human topoisomerase 1 (TOP1) in regulation of G-quadruplex (G4) formation in the Pu27 region of the MYC P1 promoter. Pu27 is among the best characterized G4 forming sequences in the human genome and it is well known that promoter activity is inhibited upon G4 formation in this region. We found that TOP1 downregulation stimulated transcription from a promoter with wildtype Pu27 but not if the G4 motif in Pu27 was interrupted by mutation(s). The effect was not specific to the MYC promoter and similar results were obtained for the G4 forming promoter element WT21. The other major DNA topoisomerases with relaxation activity, topoisomerases 2α and β, on the other hand, did not affect G4 dependent promoter activity. The cellular studies were supported by in vitro investigations demonstrating a high affinity of TOP1 for wildtype Pu27 but not for mutant sequences unable to form G4. Moreover, TOP1 was able to induce G4 formation in Pu27 inserted in double stranded plasmid DNA in vitro. This is the first time TOP1 has been demonstrated capable of inducing G4 formation in double stranded DNA and of influencing G4 formation in cells. Oxford University Press 2022-06-10 /pmc/articles/PMC9226537/ /pubmed/35687110 http://dx.doi.org/10.1093/nar/gkac482 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Molecular Biology
Keller, Josephine Geertsen
Hymøller, Kirstine Mejlstrup
Thorsager, Maria Eriksen
Hansen, Noriko Y
Erlandsen, Jens Uldum
Tesauro, Cinzia
Simonsen, Anne Katrine W
Andersen, Anne Bech
Vandsø Petersen, Kamilla
Holm, Lise Lolle
Stougaard, Magnus
Andresen, Brage Storstein
Kristensen, Peter
Frøhlich, Rikke
Knudsen, Birgitta R
Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title_full Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title_fullStr Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title_full_unstemmed Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title_short Topoisomerase 1 inhibits MYC promoter activity by inducing G-quadruplex formation
title_sort topoisomerase 1 inhibits myc promoter activity by inducing g-quadruplex formation
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226537/
https://www.ncbi.nlm.nih.gov/pubmed/35687110
http://dx.doi.org/10.1093/nar/gkac482
work_keys_str_mv AT kellerjosephinegeertsen topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT hymøllerkirstinemejlstrup topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT thorsagermariaeriksen topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT hansennorikoy topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT erlandsenjensuldum topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT tesaurocinzia topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT simonsenannekatrinew topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT andersenannebech topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT vandsøpetersenkamilla topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT holmliselolle topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT stougaardmagnus topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT andresenbragestorstein topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT kristensenpeter topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT frøhlichrikke topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation
AT knudsenbirgittar topoisomerase1inhibitsmycpromoteractivitybyinducinggquadruplexformation