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

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

Nature Communications

10.1038/s41467-023-42078-9

http://dx.doi.org/10.1038/s41467-023-42078-9

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, Wee-Wei Tee

13 October 2023

Lau, M. S., Hu, Z., Zhao, X., Tan, Y. S., Liu, J., Huang, H., Yeo, C. J., Leong, H. F., Grinchuk, O. V., Chan, J. K., Yan, J., & Tee, W.-W. (2023). Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-42078-9

AbstractRegulation 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR Research Office - Career Development Fund (CDF)
Grant Reference no. : 212D800076

This research / project is supported by the Singapore Ministry of Education - Academic Research Funds Tier 2
Grant Reference no. : MOE-T2EP50220-0015

This research / project is supported by the National Research Foundation (NRF) - NRF Fellowship program
Grant Reference no. : NRF-NRFF2016-06

This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant (OFIRG)
Grant Reference no. : OFIRG19nov-0015

This research / project is supported by the National University Health System - NUHS Seed Fund
Grant Reference no. : NUHSRO/2020/030/T1/Seed-Aug/14

https://oar.a-star.edu.sg/communities-collections/articles/20144

2041-1723

Institute of Molecular and Cell Biology