Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription
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-enzymat...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42078-9 |
| _version_ | 1797557917510008832 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mei Sheng Lau |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:23:02Z |
| format | Article |
| id | doaj.art-07b9f7d58a174f738ea42b0c54df09f6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:23:02Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-07b9f7d58a174f738ea42b0c54df09f62023-11-20T10:16:10ZengNature PortfolioNature Communications2041-17232023-10-0114111710.1038/s41467-023-42078-9Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscriptionMei Sheng Lau0Zhenhua Hu1Xiaodan Zhao2Yaw Sing Tan3Jinyue Liu4Hua Huang5Clarisse Jingyi Yeo6Hwei Fen Leong7Oleg V. Grinchuk8Justin Kaixuan Chan9Jie Yan10Wee-Wei Tee11Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Department of Physics, National University of SingaporeBioinformatics Institute (BII), A*STARGenome Institute of Singapore (GIS), A*STARDepartment of Physiology, Yong Loo Lin School of Medicine, National University of SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)Department of Physics, National University of SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)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.https://doi.org/10.1038/s41467-023-42078-9 |
| spellingShingle | 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 Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription Nature Communications |
| title | Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription |
| title_full | Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription |
| title_fullStr | Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription |
| title_full_unstemmed | Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription |
| title_short | Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription |
| title_sort | transcriptional repression by a secondary dna binding surface of dna topoisomerase i safeguards against hypertranscription |
| url | https://doi.org/10.1038/s41467-023-42078-9 |
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