G-quadruplexes on chromosomal DNA negatively regulates topoisomerase 1 activity
© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research..
Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:52 |
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| Enthalten in: |
Nucleic acids research - 52(2024), 5 vom: 21. März, Seite 2142-2156 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liang, Hui-Ting [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 26.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/nar/gkae073 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1 | ||
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| 700 | 1 | |a Zhang, Xue-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Xing, Zhi-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lin |e verfasserin |4 aut | |
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| 700 | 1 | |a Li, Guo-Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a He, Yi-de |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Ke-Wei |e verfasserin |4 aut | |
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