Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics
Abstract Type IA topoisomerases (TopoIAs) are present in all living organisms. They resolve DNA/RNA catenanes, knots and supercoils by breaking and rejoining single-stranded DNA/RNA segments and allowing the passage of another nucleic acid segment through the break. Topoisomerase III-β (TOP3B), the...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55959-y |
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| author | Xi Yang Xuemin Chen Wei Yang Yves Pommier |
| author_facet | Xi Yang Xuemin Chen Wei Yang Yves Pommier |
| author_sort | Xi Yang |
| collection | DOAJ |
| description | Abstract Type IA topoisomerases (TopoIAs) are present in all living organisms. They resolve DNA/RNA catenanes, knots and supercoils by breaking and rejoining single-stranded DNA/RNA segments and allowing the passage of another nucleic acid segment through the break. Topoisomerase III-β (TOP3B), the only RNA topoisomerase in metazoans, promotes R-loop disassembly and translation of mRNAs. Defects in TOP3B lead to severe neurological diseases. We present a series of cryo-EM structures of human TOP3B with its cofactor TDRD3 during cleavage and rejoining of DNA or RNA, thus elucidating the roles of divalent metal ions and key enzyme residues in each step of the catalytic cycle. We also obtained the structure of an open-gate configuration that addresses the long-standing question of the strand-passage mechanism. Our studies reveal how TOP3B catalyzes both DNA and RNA relaxation, while TOP3A acts only on DNA. |
| format | Article |
| id | doaj-art-e409cf9e464748ec9cb1d90fc1856ee2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e409cf9e464748ec9cb1d90fc1856ee22025-01-26T12:40:34ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-025-55959-yStructural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamicsXi Yang0Xuemin Chen1Wei Yang2Yves Pommier3Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIHLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIHLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIHDevelopmental Therapeutics Branch & Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIHAbstract Type IA topoisomerases (TopoIAs) are present in all living organisms. They resolve DNA/RNA catenanes, knots and supercoils by breaking and rejoining single-stranded DNA/RNA segments and allowing the passage of another nucleic acid segment through the break. Topoisomerase III-β (TOP3B), the only RNA topoisomerase in metazoans, promotes R-loop disassembly and translation of mRNAs. Defects in TOP3B lead to severe neurological diseases. We present a series of cryo-EM structures of human TOP3B with its cofactor TDRD3 during cleavage and rejoining of DNA or RNA, thus elucidating the roles of divalent metal ions and key enzyme residues in each step of the catalytic cycle. We also obtained the structure of an open-gate configuration that addresses the long-standing question of the strand-passage mechanism. Our studies reveal how TOP3B catalyzes both DNA and RNA relaxation, while TOP3A acts only on DNA.https://doi.org/10.1038/s41467-025-55959-y |
| spellingShingle | Xi Yang Xuemin Chen Wei Yang Yves Pommier Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics Nature Communications |
| title | Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics |
| title_full | Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics |
| title_fullStr | Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics |
| title_full_unstemmed | Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics |
| title_short | Structural insights into human topoisomerase 3β DNA and RNA catalysis and nucleic acid gate dynamics |
| title_sort | structural insights into human topoisomerase 3β dna and rna catalysis and nucleic acid gate dynamics |
| url | https://doi.org/10.1038/s41467-025-55959-y |
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