Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription

Mei Sheng Lau (), Zhenhua Hu, Xiaodan Zhao, Yaw Sing Tan, Jinyue Liu, Hua Huang, Clarisse Jingyi Yeo, Hwei Fen Leong, Oleg V. Grinchuk, Justin Kaixuan Chan, Jie Yan () and Wee-Wei Tee ()
Additional contact information
Mei Sheng Lau: Technology and Research (A*STAR)
Zhenhua Hu: Technology and Research (A*STAR)
Xiaodan Zhao: National University of Singapore
Yaw Sing Tan: Bioinformatics Institute (BII), A*STAR
Jinyue Liu: Genome Institute of Singapore (GIS), A*STAR
Hua Huang: National University of Singapore
Clarisse Jingyi Yeo: Technology and Research (A*STAR)
Hwei Fen Leong: Technology and Research (A*STAR)
Oleg V. Grinchuk: Technology and Research (A*STAR)
Justin Kaixuan Chan: Technology and Research (A*STAR)
Jie Yan: National University of Singapore
Wee-Wei Tee: Technology and Research (A*STAR)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis. This function is dependent on specific DNA-interacting residues located on a conserved protein surface. A loss-of-function knock-in mutation on this surface, R548Q, is sufficient to cause hypertranscription and alter differentiation outcomes in mouse embryonic stem cells (mESCs). Hypertranscription in mESCs is accompanied by reduced TOP1 chromatin binding and change in genomic supercoiling. Notably, the mutation does not impact TOP1 enzymatic activity; rather, it diminishes TOP1-DNA binding and formation of compact protein-DNA structures. Thus, TOP1 exhibits opposing influences on transcription through distinct activities which are likely to be coordinated. This highlights TOP1 as a safeguard of appropriate total transcription levels in cells.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42078-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42078-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42078-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().