Human Smc5/6 recognises transcription-generated positive DNA supercoils

Article Article scientifique Article Human Smc5/6 recognises transcription-generated positive DNA supercoils eng 2024-09-06 2024-09-06 author Diman Aurélie 0000-0003-2158-4802 Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. aurelie.diman@gmail.com.,Geneva Centre for Inflammation Research (GCIR), Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. aurelie.diman@gmail.com. 911321 Département de microbiologie et médecine moléculaire (MIMOL) author Panis Gaël Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.,Geneva Centre for Inflammation Research (GCIR), Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. 743525 Département de microbiologie et médecine moléculaire (MIMOL) author Castrogiovanni Cédric 0000-0003-3219-7306 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.,Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. 913443 author Prados Julien 0000-0002-8546-241X Bioinformatics Support Platform, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. 561771 Services communs de la faculté de médecine (SCMU) author Baechler Bastien Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.,Geneva Centre for Inflammation Research (GCIR), Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. 843251 Département de pathologie et immunologie (PATIM) author Strubin Michel Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.,Geneva Centre for Inflammation Research (GCIR), Faculty of Medicine, University of Geneva, Geneva 4, Switzerland. 22429 Décanat et administration de la faculté de médecine (ADMED) 7805 10.1038/s41467-024-50646-w 39242537 2041-1723 PMC11379904 https://www.nature.com/articles/s41467-024-50646-w Beyond its essential roles in ensuring faithful chromosome segregation and genomic stability, the human Smc5/6 complex acts as an antiviral factor. It binds to and impedes the transcription of extrachromosomal DNA templates; an ability which is lost upon integration of the DNA into the chromosome. How the complex distinguishes among different DNA templates is unknown. Here we show that, in human cells, Smc5/6 preferentially binds to circular rather than linear extrachromosomal DNA. We further demonstrate that the transcriptional process, per se, and particularly the accumulation of DNA secondary structures known to be substrates for topoisomerases, is responsible for Smc5/6 recruitment. More specifically, we find that in vivo Smc5/6 binds to positively supercoiled DNA. Those findings, in conjunction with our genome-wide Smc5/6 binding analysis showing that Smc5/6 localizes at few but highly transcribed chromosome loci, not only unveil a previously unforeseen role of Smc5/6 in DNA topology management during transcription but highlight the significance of sensing DNA topology as an antiviral defense mechanism. Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Chromosomal Proteins, Non-Histone / genetics Chromosomal Proteins, Non-Histone / metabolism DNA / genetics DNA / metabolism DNA, Circular / genetics DNA, Circular / metabolism DNA, Superhelical / genetics DNA, Superhelical / metabolism Humans Nucleic Acid Conformation Protein Binding Transcription, Genetic Dewey 612 Dewey 616 Swiss National Science Foundation Role of hepatitis B virus X protein during viral infection and associated liver cancer 149626 CH Projects Swiss National Science Foundation The Smc5/6 complex as an antiviral restriction factor: how does it work and how does hepatitis B virus fight back? 175781 CH Projects 54 Département de microbiologie et médecine moléculaire 21B 134 Département de physiologie cellulaire et métabolisme 21C false 230 Régulation de l'expression des gènes du virus de l'hépatite B 294 365 Régulation traductionnelle dans les cellules de mammifère 631 48a82112-9f30-4dde-a32a-47c02fceac29 Bioinformatics Support Platform 0a6434c9-7972-44ea-8708-82e501660dc7 Biomedical Data Science Facility 0a6434c9-7972-44ea-8708-82e501660dc7 Biomedical Data Science Facility https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231328 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE212468 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136943 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89413 Nature communications 15 1 816b6b78-37b8-4038-aca1-36f21992fda3 Article (Published version) Public Article_scientifique_from_crossref.pdf 2898563 application/pdf CC BY-NC-ND-4.0 e62ddb131f8444745881ffc6dcbeda62d8951098f83484d737fc1e7dc5f4922d bc652e71-cc76-4773-9476-22edb4164d1b Supplemental data Public 41467_2024_50646_MOESM1_ESM.pdf 903597 application/pdf bdea68a415cbe5a5231e1e0cd37a7cd93fef25d09001afb1bcf666b3cfd962fc e48a20eb-1783-40bb-ad54-01e6b42bd16c Supplemental data Public 41467_2024_50646_MOESM4_ESM.xlsx 3795520 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 4af1198536eac22fe615a0fc23939674556f824aa3651a75b5684fe40abd8ddd openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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