[{"fulldoi":"https://doi.org/10.1038/s41594-024-01448-7","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","oa":1,"project":[{"name":"Regulation of mammalian transcription by noncoding RNA","_id":"c08a6700-5a5b-11eb-8a69-82a722b2bc30","grant_number":"P34185"}],"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":32,"date_created":"2025-01-08T11:20:20Z","day":"01","ddc":["570"],"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"EM-Fac"},{"_id":"ScienComp"},{"_id":"PreCl"}],"_id":"18778","scopus_import":"1","language":[{"iso":"eng"}],"corr_author":"1","oa_version":"Published Version","quality_controlled":"1","citation":{"ama":"Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional repression by noncoding RNA. <i>Nature Structural &#38; Molecular Biology</i>. 2025;32:607-612. doi:<a href=\"https://doi.org/10.1038/s41594-024-01448-7\">10.1038/s41594-024-01448-7</a>","ista":"Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. 2025. Mechanism of mammalian transcriptional repression by noncoding RNA. Nature Structural &#38; Molecular Biology. 32, 607–612.","mla":"Tluckova, Katarina, et al. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.” <i>Nature Structural &#38; Molecular Biology</i>, vol. 32, Springer Nature, 2025, pp. 607–12, doi:<a href=\"https://doi.org/10.1038/s41594-024-01448-7\">10.1038/s41594-024-01448-7</a>.","short":"K. Tluckova, B.M. Kaczmarek, A.P. Testa Salmazo, C. Bernecky, Nature Structural &#38; Molecular Biology 32 (2025) 607–612.","ieee":"K. Tluckova, B. M. Kaczmarek, A. P. Testa Salmazo, and C. Bernecky, “Mechanism of mammalian transcriptional repression by noncoding RNA,” <i>Nature Structural &#38; Molecular Biology</i>, vol. 32. Springer Nature, pp. 607–612, 2025.","apa":"Tluckova, K., Kaczmarek, B. M., Testa Salmazo, A. P., &#38; Bernecky, C. (2025). Mechanism of mammalian transcriptional repression by noncoding RNA. <i>Nature Structural &#38; Molecular Biology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41594-024-01448-7\">https://doi.org/10.1038/s41594-024-01448-7</a>","chicago":"Tluckova, Katarina, Beata M Kaczmarek, Anita P Testa Salmazo, and Carrie Bernecky. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.” <i>Nature Structural &#38; Molecular Biology</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1038/s41594-024-01448-7\">https://doi.org/10.1038/s41594-024-01448-7</a>."},"isi":1,"page":"607-612","OA_place":"publisher","author":[{"full_name":"Tluckova, Katarina","first_name":"Katarina","last_name":"Tluckova","id":"4AC7D980-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Kaczmarek","id":"36FA4AFA-F248-11E8-B48F-1D18A9856A87","full_name":"Kaczmarek, Beata M","first_name":"Beata M"},{"id":"41F1F098-F248-11E8-B48F-1D18A9856A87","last_name":"Testa Salmazo","first_name":"Anita P","full_name":"Testa Salmazo, Anita P"},{"last_name":"Bernecky","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0893-7036","full_name":"Bernecky, Carrie A","first_name":"Carrie A"}],"status":"public","publisher":"Springer Nature","article_type":"original","date_published":"2025-04-01T00:00:00Z","external_id":{"isi":["001390268000001"],"pmid":["39762629"]},"publication_identifier":{"issn":["1545-9993"],"eissn":["1545-9985"]},"doi":"10.1038/s41594-024-01448-7","file_date_updated":"2025-04-16T08:17:27Z","department":[{"_id":"CaBe"}],"type":"journal_article","pmid":1,"article_processing_charge":"Yes (in subscription journal)","OA_type":"hybrid","acknowledgement":"We thank the members of the Bernecky laboratory for helpful discussions and A. Hlavata for providing Pol II for use in the fluorescence anisotropy binding assay. We thank V.-V. Hodirnau for SerialEM data collection and support with EPU data collection. We thank D. Slade (Max Perutz Laboratories and Medical University of Vienna, Vienna, Austria) for the wild-type TFIIF expression plasmid. We thank N. Thompson and R. Burgess (McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA) for the 8WG16 hybridoma cell line. We thank C. Plaschka and M. Loose for critical reading of the manuscript. This work was supported by Austrian Science Fund (FWF) grant no. P34185 (DOI 10.55776/P34185) (C.B.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This research was further supported by the Scientific Service Units of ISTA through resources provided by the Laboratory Support Facility, Electron Microscopy Facility, Scientific Computing and the Preclinical Facility.","publication":"Nature Structural & Molecular Biology","file":[{"relation":"main_file","success":1,"creator":"dernst","checksum":"2919b30b271f395888e880076a680d73","content_type":"application/pdf","file_size":9306639,"date_created":"2025-04-16T08:17:27Z","file_id":"19573","access_level":"open_access","date_updated":"2025-04-16T08:17:27Z","file_name":"2025_NatureStrucMolBiol_Tluckova.pdf"}],"month":"04","date_updated":"2025-11-20T10:28:36Z","license":"https://creativecommons.org/licenses/by/4.0/","abstract":[{"lang":"eng","text":"Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryogenic-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how distinct domains of the general transcription factor TFIIF control repressive activity. Together, we reveal how a noncoding RNA can regulate mammalian gene expression."}],"APC_amount":"12348 EUR","year":"2025","has_accepted_license":"1","title":"Mechanism of mammalian transcriptional repression by noncoding RNA","intvolume":"        32","related_material":{"record":[{"id":"14644","status":"public","relation":"earlier_version"}]}},{"quality_controlled":"1","isi":1,"citation":{"ista":"Ramadhin AR, Lee S-H, Zhou D, Testa Salmazo AP, Gonzalo-Hansen C, van Sluis M, Blom CMA, Janssens RC, Raams A, Dekkers D, Bezstarosti K, Slade D, Vermeulen W, Pines A, Demmers JAA, Bernecky C, Sixma TK, Marteijn JA. 2024. STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. Molecular Cell. 84(24), 4740–4757.e12.","mla":"Ramadhin, Anisha R., et al. “STK19 Drives Transcription-Coupled Repair by Stimulating Repair Complex Stability, RNA Pol II Ubiquitylation, and TFIIH Recruitment.” <i>Molecular Cell</i>, vol. 84, no. 24, Elsevier, 2024, p. 4740–4757.e12, doi:<a href=\"https://doi.org/10.1016/j.molcel.2024.10.030\">10.1016/j.molcel.2024.10.030</a>.","ama":"Ramadhin AR, Lee S-H, Zhou D, et al. STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. <i>Molecular Cell</i>. 2024;84(24):4740-4757.e12. doi:<a href=\"https://doi.org/10.1016/j.molcel.2024.10.030\">10.1016/j.molcel.2024.10.030</a>","apa":"Ramadhin, A. R., Lee, S.-H., Zhou, D., Testa Salmazo, A. P., Gonzalo-Hansen, C., van Sluis, M., … Marteijn, J. A. (2024). STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. <i>Molecular Cell</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.molcel.2024.10.030\">https://doi.org/10.1016/j.molcel.2024.10.030</a>","chicago":"Ramadhin, Anisha R., Shun-Hsiao Lee, Di Zhou, Anita P Testa Salmazo, Camila Gonzalo-Hansen, Marjolein van Sluis, Cindy M.A. Blom, et al. “STK19 Drives Transcription-Coupled Repair by Stimulating Repair Complex Stability, RNA Pol II Ubiquitylation, and TFIIH Recruitment.” <i>Molecular Cell</i>. Elsevier, 2024. <a href=\"https://doi.org/10.1016/j.molcel.2024.10.030\">https://doi.org/10.1016/j.molcel.2024.10.030</a>.","short":"A.R. Ramadhin, S.-H. Lee, D. Zhou, A.P. Testa Salmazo, C. Gonzalo-Hansen, M. van Sluis, C.M.A. Blom, R.C. Janssens, A. Raams, D. Dekkers, K. Bezstarosti, D. Slade, W. Vermeulen, A. Pines, J.A.A. Demmers, C. Bernecky, T.K. Sixma, J.A. Marteijn, Molecular Cell 84 (2024) 4740–4757.e12.","ieee":"A. R. Ramadhin <i>et al.</i>, “STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment,” <i>Molecular Cell</i>, vol. 84, no. 24. Elsevier, p. 4740–4757.e12, 2024."},"OA_place":"publisher","author":[{"last_name":"Ramadhin","first_name":"Anisha R.","full_name":"Ramadhin, Anisha R."},{"full_name":"Lee, Shun-Hsiao","first_name":"Shun-Hsiao","last_name":"Lee"},{"last_name":"Zhou","full_name":"Zhou, Di","first_name":"Di"},{"full_name":"Testa Salmazo, Anita P","first_name":"Anita P","last_name":"Testa Salmazo","id":"41F1F098-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Camila","full_name":"Gonzalo-Hansen, Camila","last_name":"Gonzalo-Hansen"},{"first_name":"Marjolein","full_name":"van Sluis, Marjolein","last_name":"van Sluis"},{"first_name":"Cindy M.A.","full_name":"Blom, Cindy M.A.","last_name":"Blom"},{"full_name":"Janssens, Roel C.","first_name":"Roel C.","last_name":"Janssens"},{"last_name":"Raams","full_name":"Raams, Anja","first_name":"Anja"},{"last_name":"Dekkers","full_name":"Dekkers, Dick","first_name":"Dick"},{"last_name":"Bezstarosti","full_name":"Bezstarosti, Karel","first_name":"Karel"},{"last_name":"Slade","full_name":"Slade, Dea","first_name":"Dea"},{"first_name":"Wim","full_name":"Vermeulen, Wim","last_name":"Vermeulen"},{"last_name":"Pines","full_name":"Pines, Alex","first_name":"Alex"},{"full_name":"Demmers, Jeroen A.A.","first_name":"Jeroen A.A.","last_name":"Demmers"},{"first_name":"Carrie A","full_name":"Bernecky, Carrie A","orcid":"0000-0003-0893-7036","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","last_name":"Bernecky"},{"last_name":"Sixma","first_name":"Titia K.","full_name":"Sixma, Titia K."},{"first_name":"Jurgen A.","full_name":"Marteijn, Jurgen A.","last_name":"Marteijn"}],"page":"4740-4757.e12","status":"public","publisher":"Elsevier","article_type":"original","date_published":"2024-12-19T00:00:00Z","external_id":{"isi":["001395711300001"],"pmid":["39547223"]},"publication_identifier":{"issn":["1097-2765"]},"file_date_updated":"2025-01-13T11:17:35Z","doi":"10.1016/j.molcel.2024.10.030","department":[{"_id":"CaBe"}],"fulldoi":"https://doi.org/10.1016/j.molcel.2024.10.030","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","oa":1,"publication_status":"published","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":84,"dataavailabilitystatement":"Proteomics data is deposited at the ProteomeXchange Consortium through the PRIDE partner repository with dataset identifier PXD051720. Imaging data are deposited at Mendeley Data at https://doi.org/10.17632/wp9sf6sp4z.1. Cryo-EM reconstructions and structure coordinates are deposited to the Electron Microscopy Database (EMDB) and to the PDB under the following accession codes: for RNA Pol II-TC-NER-STK19 complex model (PDB: 9FD2), composite map (EMD-50325) and consensus map (EMD-50292). Focused maps of CSA-DDB1-DDA1-UVSSA-STK19 (EMD-50293), RNA Pol II-ELOF1 (EMD-50294), CRL4CSA (EMD-50295), and CSA-DDB1-DDA1-CSB (EMD-50306).\r\nThis paper does not report original code.\r\nAny additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.","date_created":"2024-11-15T12:12:54Z","day":"19","ddc":["570"],"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"PreCl"}],"_id":"18553","scopus_import":"1","language":[{"iso":"eng"}],"oa_version":"Published Version","publication":"Molecular Cell","month":"12","file":[{"file_name":"2024_MolecularCell_Ramadhin.pdf","date_updated":"2025-01-13T11:17:35Z","access_level":"open_access","file_id":"18844","checksum":"e051e2766b2d424983778f742cb7c5ed","content_type":"application/pdf","date_created":"2025-01-13T11:17:35Z","file_size":25071994,"success":1,"relation":"main_file","creator":"dernst"}],"date_updated":"2026-10-01T08:20:39Z","researchdata_availability":"yes","abstract":[{"lang":"eng","text":"Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4CSA serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. However, the precise regulatory mechanisms of CRL4CSA activity and TFIIH recruitment remain elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a TC-NER factor, which is essential for correct DNA damage removal and subsequent transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA, UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability and CRL4CSA activity, resulting in efficient RNA Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core TC-NER component."}],"year":"2024","has_accepted_license":"1","intvolume":"        84","title":"STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment","related_material":{"record":[{"id":"23013","status":"public","relation":"research_data"}]},"type":"journal_article","pmid":1,"article_processing_charge":"No","OA_type":"hybrid","acknowledgement":"We thank N. Thompson and R. Burgess for the 8WG16 hybridoma cell line. This research was further supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Lab Support Facility (LSF) and the Preclinical Facility (PCF). This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. Research at the Netherlands Cancer Institute is supported by institutional grants of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport. This study was supported by a VICI (VI.C.182.025) and a TOP Grant (714.017.003) of the Netherlands Organization for Scientific Research.","issue":"24","supplementarymaterial":"yes","das_tickbox":"1"},{"publication_status":"published","volume":67,"dataavailabilitystatement":"Atomic coordinates and experimental data have been deposited in the PDB with the following PDB ID codes: 6CNX (VRK1 bound to 2); 6CFM (VRK1 bound to 3); 6CQH (VRK1 bound to 4); 6CMM (VRK1 bound to 7); 6VXU (VRK1 bound to 8); 6VZH (VRK1 bound to 11); 6CSW (VRK1 bound to 13); 8V42 (VRK1 bound to 21); 6NPN (VRK1 bound to 24).","fulldoi":"https://doi.org/10.1021/acs.jmedchem.3c02250","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","_id":"18945","oa_version":"None","language":[{"iso":"eng"}],"scopus_import":"1","date_created":"2025-01-29T09:14:19Z","day":"23","status":"public","publisher":"American Chemical Society","citation":{"ama":"de Souza Gama FH, Dutra LA, Hawgood M, et al. Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. <i>Journal of Medicinal Chemistry</i>. 2024;67(11):8609-8629. doi:<a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">10.1021/acs.jmedchem.3c02250</a>","ista":"de Souza Gama FH, Dutra LA, Hawgood M, dos Reis CV, Serafim RAM, Ferreira MA, Teodoro BVM, Takarada JE, Santiago AS, Balourdas D-I, Nilsson A-S, Urien B, Almeida VM, Gileadi C, Ramos PZ, Testa Salmazo AP, Vasconcelos SNS, Cunha MR, Mueller S, Knapp S, Massirer KB, Elkins JM, Gileadi O, Mascarello A, Lemmens BBLG, Guimarães CRW, Azevedo H, Couñago RM. 2024. Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. 67(11), 8609–8629.","mla":"de Souza Gama, Fernando H., et al. “Novel Dihydropteridinone Derivatives as Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.” <i>Journal of Medicinal Chemistry</i>, vol. 67, no. 11, American Chemical Society, 2024, pp. 8609–29, doi:<a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">10.1021/acs.jmedchem.3c02250</a>.","short":"F.H. de Souza Gama, L.A. Dutra, M. Hawgood, C.V. dos Reis, R.A.M. Serafim, M.A. Ferreira, B.V.M. Teodoro, J.E. Takarada, A.S. Santiago, D.-I. Balourdas, A.-S. Nilsson, B. Urien, V.M. Almeida, C. Gileadi, P.Z. Ramos, A.P. Testa Salmazo, S.N.S. Vasconcelos, M.R. Cunha, S. Mueller, S. Knapp, K.B. Massirer, J.M. Elkins, O. Gileadi, A. Mascarello, B.B.L.G. Lemmens, C.R.W. Guimarães, H. Azevedo, R.M. Couñago, Journal of Medicinal Chemistry 67 (2024) 8609–8629.","ieee":"F. H. de Souza Gama <i>et al.</i>, “Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε,” <i>Journal of Medicinal Chemistry</i>, vol. 67, no. 11. American Chemical Society, pp. 8609–8629, 2024.","apa":"de Souza Gama, F. H., Dutra, L. A., Hawgood, M., dos Reis, C. V., Serafim, R. A. M., Ferreira, M. A., … Couñago, R. M. (2024). Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε. <i>Journal of Medicinal Chemistry</i>. American Chemical Society. <a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">https://doi.org/10.1021/acs.jmedchem.3c02250</a>","chicago":"Souza Gama, Fernando H. de, Luiz A. Dutra, Michael Hawgood, Caio Vinícius dos Reis, Ricardo A. M. Serafim, Marcos A. Ferreira, Bruno V. M. Teodoro, et al. “Novel Dihydropteridinone Derivatives as Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.” <i>Journal of Medicinal Chemistry</i>. American Chemical Society, 2024. <a href=\"https://doi.org/10.1021/acs.jmedchem.3c02250\">https://doi.org/10.1021/acs.jmedchem.3c02250</a>."},"quality_controlled":"1","page":"8609-8629","author":[{"first_name":"Fernando H.","full_name":"de Souza Gama, Fernando H.","last_name":"de Souza Gama"},{"last_name":"Dutra","full_name":"Dutra, Luiz A.","first_name":"Luiz A."},{"first_name":"Michael","full_name":"Hawgood, Michael","last_name":"Hawgood"},{"first_name":"Caio Vinícius","full_name":"dos Reis, Caio Vinícius","last_name":"dos Reis"},{"last_name":"Serafim","full_name":"Serafim, Ricardo A. M.","first_name":"Ricardo A. M."},{"last_name":"Ferreira","first_name":"Marcos A.","full_name":"Ferreira, Marcos A."},{"first_name":"Bruno V. M.","full_name":"Teodoro, Bruno V. M.","last_name":"Teodoro"},{"first_name":"Jéssica Emi","full_name":"Takarada, Jéssica Emi","last_name":"Takarada"},{"last_name":"Santiago","full_name":"Santiago, André S.","first_name":"André S."},{"last_name":"Balourdas","full_name":"Balourdas, Dimitrios-Ilias","first_name":"Dimitrios-Ilias"},{"first_name":"Ann-Sofie","full_name":"Nilsson, Ann-Sofie","last_name":"Nilsson"},{"full_name":"Urien, Bruno","first_name":"Bruno","last_name":"Urien"},{"last_name":"Almeida","full_name":"Almeida, Vitor M.","first_name":"Vitor M."},{"first_name":"Carina","full_name":"Gileadi, Carina","last_name":"Gileadi"},{"last_name":"Ramos","full_name":"Ramos, Priscila Z.","first_name":"Priscila Z."},{"last_name":"Testa Salmazo","id":"41F1F098-F248-11E8-B48F-1D18A9856A87","full_name":"Testa Salmazo, Anita P","first_name":"Anita P"},{"last_name":"Vasconcelos","full_name":"Vasconcelos, Stanley N. S.","first_name":"Stanley N. S."},{"first_name":"Micael R.","full_name":"Cunha, Micael R.","last_name":"Cunha"},{"last_name":"Mueller","first_name":"Susanne","full_name":"Mueller, Susanne"},{"full_name":"Knapp, Stefan","first_name":"Stefan","last_name":"Knapp"},{"first_name":"Katlin B.","full_name":"Massirer, Katlin B.","last_name":"Massirer"},{"last_name":"Elkins","first_name":"Jonathan M.","full_name":"Elkins, Jonathan M."},{"full_name":"Gileadi, Opher","first_name":"Opher","last_name":"Gileadi"},{"last_name":"Mascarello","first_name":"Alessandra","full_name":"Mascarello, Alessandra"},{"last_name":"Lemmens","full_name":"Lemmens, Bennie B. L. G.","first_name":"Bennie B. L. G."},{"last_name":"Guimarães","full_name":"Guimarães, Cristiano R. W.","first_name":"Cristiano R. W."},{"last_name":"Azevedo","first_name":"Hatylas","full_name":"Azevedo, Hatylas"},{"full_name":"Couñago, Rafael M.","first_name":"Rafael M.","last_name":"Couñago"}],"department":[{"_id":"CaBe"}],"doi":"10.1021/acs.jmedchem.3c02250","article_type":"original","publication_identifier":{"issn":["0022-2623"],"eissn":["1520-4804"]},"external_id":{"pmid":["38780468"]},"date_published":"2024-05-23T00:00:00Z","article_processing_charge":"No","OA_type":"closed access","type":"journal_article","pmid":1,"das_tickbox":"1","supplementarymaterial":"yes","acknowledgement":"R.M.C. and K.B.M. are grateful for support by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) (grants 2013/50724–5 and 2014/50897–0), Embrapii (Empresa Brasileira de Pesquisa e Inovação Industrial), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) (grant 465651/2014–3) and Aché Laboratórios Farmacêuticos. R.M.C. and O.G. are also grateful for support by the Structural Genomics Consortium, a registered charity (1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through the Ontario Genomics Institute (OGI-196), EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN Grant 875510), Janssen, Merck KGaA, Merck & Co., Pfizer, Takeda, and Wellcome. B.L. and M.H. are grateful for support from the Swedish Research Council, Swedish Cancer Society, Karolinska Institutet and The Mark Foundation for Cancer Research. R.A.M.S. (2016/25320–6 and 2018/23322–7), A.S.S. (2019/14275–8), S.N.S.V (2018/09475–5), V.M.A. (2022/00743–2) and M.R.C. (2021/04853–4) were recipients of fellowships from the Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP. C.V.R. (88887.146077/2017–00), J.E.T. (88887.373547/2019–00) and P.Z.R (88887.136432/2017–00) were the recipient of fellowships from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES.\r\nWe thank all members of CQMED-UNICAMP for their help and support. We thank the staff of the Life Sciences Core Facility (LaCTAD) at UNICAMP for the Genomics and Mass Spectrometry analysis. We thank the NMR facility at UNICAMP Chemistry Institute for its assistance. We thank the staff at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6M detector on the 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source; a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Diamond Light Source for access to beamline I24. The authors thank Tammy Havener (SGC-UNC), Abid Hussain Sayyid (KI), and Yiqiu Yang (KI) for valuable discussions and technical support.","issue":"11","publication":"Journal of Medicinal Chemistry","researchdata_availability":"yes","date_updated":"2026-10-01T08:26:28Z","month":"05","intvolume":"        67","title":"Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε","abstract":[{"text":"Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.","lang":"eng"}],"year":"2024"},{"year":"2023","license":"https://creativecommons.org/licenses/by-nc/4.0/","abstract":[{"text":"Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryo-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how domains of the general transcription factor TFIIF affect complex dynamics and control repressive activity. Together, we reveal how a non-coding RNA can regulate mammalian gene expression.","lang":"eng"}],"related_material":{"record":[{"id":"18778","status":"public","relation":"later_version"}]},"title":"Mechanism of mammalian transcriptional repression by noncoding RNA","has_accepted_license":"1","date_updated":"2025-11-20T10:28:37Z","month":"12","file":[{"date_updated":"2023-12-05T10:37:02Z","file_name":"2023_Tluckova_etal_REx.pdf","file_id":"14646","access_level":"open_access","checksum":"c45608cb97ee36d7b50ba518db8e07b0","content_type":"application/pdf","file_size":4892920,"date_created":"2023-12-05T10:37:02Z","relation":"main_file","success":1,"creator":"dernst"}],"acknowledgement":"We thank B. Kaczmarek and other members of the Bernecky lab for helpful discussions. We thank V.-V. Hodirnau for SerialEM data collection and support with EPU data collection. We thank D. Slade for the wild type TFIIF expression\r\nplasmid. We thank N. Thompson and R. Burgess for the 8WG16 hybridoma cell line. We thank C. Plaschka and M. Loose for critical reading of the manuscript. This work was supported by Austrian Science Fund (FWF) grant P34185. This research was further supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Lab Support Facility (LSF), Electron Microscopy Facility (EMF), Scientific Computing (SciComp), and the Preclinical Facility (PCF).","type":"preprint","article_processing_charge":"No","date_published":"2023-12-05T00:00:00Z","doi":"10.15479/AT:ISTA:14644","file_date_updated":"2023-12-05T10:37:02Z","author":[{"full_name":"Tluckova, Katarina","first_name":"Katarina","last_name":"Tluckova","id":"4AC7D980-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Anita P","full_name":"Testa Salmazo, Anita P","id":"41F1F098-F248-11E8-B48F-1D18A9856A87","last_name":"Testa Salmazo"},{"full_name":"Bernecky, Carrie A","first_name":"Carrie A","last_name":"Bernecky","id":"2CB9DFE2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0893-7036"}],"citation":{"mla":"Tluckova, Katarina, et al. <i>Mechanism of Mammalian Transcriptional Repression by Noncoding RNA</i>. Institute of Science and Technology Austria, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:14644\">10.15479/AT:ISTA:14644</a>.","ista":"Tluckova K, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional repression by noncoding RNA. <a href=\"https://doi.org/10.15479/AT:ISTA:14644\">10.15479/AT:ISTA:14644</a>.","ama":"Tluckova K, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional repression by noncoding RNA. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:14644\">10.15479/AT:ISTA:14644</a>","chicago":"Tluckova, Katarina, Anita P Testa Salmazo, and Carrie Bernecky. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.” Institute of Science and Technology Austria, n.d. <a href=\"https://doi.org/10.15479/AT:ISTA:14644\">https://doi.org/10.15479/AT:ISTA:14644</a>.","apa":"Tluckova, K., Testa Salmazo, A. P., &#38; Bernecky, C. (n.d.). Mechanism of mammalian transcriptional repression by noncoding RNA. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:14644\">https://doi.org/10.15479/AT:ISTA:14644</a>","ieee":"K. Tluckova, A. P. Testa Salmazo, and C. Bernecky, “Mechanism of mammalian transcriptional repression by noncoding RNA.” Institute of Science and Technology Austria.","short":"K. Tluckova, A.P. Testa Salmazo, C. Bernecky, (n.d.)."},"publisher":"Institute of Science and Technology Austria","status":"public","acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"EM-Fac"},{"_id":"PreCl"}],"ddc":["572"],"date_created":"2023-12-04T14:51:00Z","day":"05","corr_author":"1","language":[{"iso":"eng"}],"oa_version":"Submitted Version","_id":"14644","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","fulldoi":"https://doi.org/10.15479/AT:ISTA:14644","tmp":{"short":"CC BY-NC (4.0)","image":"/images/cc_by_nc.png","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode"},"project":[{"name":"Regulation of mammalian transcription by noncoding RNA","_id":"c08a6700-5a5b-11eb-8a69-82a722b2bc30","grant_number":"P34185"}],"publication_status":"draft","oa":1},{"year":"2020","abstract":[{"lang":"eng","text":"The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin–binding proteins, is fundamentally important in eukaryotes. α-Actinins are major F-actin bundlers that are inhibited by Ca2+ in nonmuscle cells. Here we report the mechanism of Ca2+-mediated regulation of Entamoeba histolytica α-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic α-actinins. Crystal structures of Ca2+-free and Ca2+-bound EhActn2 reveal a calmodulin-like domain (CaMD) uniquely inserted within the rod domain. Integrative studies reveal an exceptionally high affinity of the EhActn2 CaMD for Ca2+, binding of which can only be regulated in the presence of physiological concentrations of Mg2+. Ca2+ binding triggers an increase in protein multidomain rigidity, reducing conformational flexibility of F-actin–binding domains via interdomain cross-talk and consequently inhibiting F-actin bundling. In vivo studies uncover that EhActn2 plays an important role in phagocytic cup formation and might constitute a new drug target for amoebic dysentery."}],"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1073/pnas.191726911"}],"intvolume":"       117","title":"Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin","date_updated":"2026-06-18T17:45:21Z","month":"09","publication":"Proceedings of the National Academy of Sciences of the United States of America","issue":"36","acknowledgement":"We thank the staff of the macromolecular crystallography (MX) and SAXS beamlines at the European Synchrotron Radiation facility, Diamond, and Swiss Light Source for excellent support, and the Life Sciences Facility of the Institute of Science and Technology Austria for usage of the rheometer. We thank Life Sciences editors for editing assistance. EM data were\r\nrecorded at the EM Facility of the Vienna BioCenter Core Facilities (Austria). Confocal microscopy was carried out at the Advanced Instrument Research Facility, Jawaharlal Nehru University. K.D.-C.’s research was supported by the Initial Training Network MUZIC (ITN-MUZIC) (N°238423), Austrian Science Fund (FWF) Projects I525, I1593, P22276, P19060, and W1221, Laura Bassi Centre of Optimized Structural Studies (N°253275), a Wellcome Trust Collaborative Award (201543/Z/16/Z), COST Action BM1405, Vienna Science and Technology Fund (WWTF) Chemical Biology Project LS17-008, and Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology. K.Z., J.L.A., C.S., E.A.G., and A.S. were supported by the University of Vienna, J.K. by a Wellcome Trust Collaborative Award and by the Centre of Optimized Structural Studies, M.P. by FWF Project I1593, E.d.A.R. ITN-MUZIC, and FWF Projects I525 and I1593, and T.C.M. and L.C. by FWF Project I 2408-B22. E.A.G. acknowledges the PhD program Structure and Interaction of Biological Macromolecules. M.B. acknowledges the University Grant Commission, India, for a senior research fellowship. A.B. acknowledges a JC Bose Fellowship from the Science Engineering Research Council. ","pmid":1,"type":"journal_article","article_processing_charge":"No","publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"external_id":{"pmid":["32848067"]},"date_published":"2020-09-08T00:00:00Z","article_type":"original","department":[{"_id":"CaBe"}],"doi":"10.1073/pnas.1917269117","author":[{"full_name":"Pinotsis, Nikos","first_name":"Nikos","last_name":"Pinotsis"},{"last_name":"Zielinska","first_name":"Karolina","full_name":"Zielinska, Karolina"},{"full_name":"Babuta, Mrigya","first_name":"Mrigya","last_name":"Babuta"},{"last_name":"Arolas","first_name":"Joan L.","full_name":"Arolas, Joan L."},{"full_name":"Kostan, Julius","first_name":"Julius","last_name":"Kostan"},{"last_name":"Khan","first_name":"Muhammad Bashir","full_name":"Khan, Muhammad Bashir"},{"first_name":"Claudia","full_name":"Schreiner, Claudia","last_name":"Schreiner"},{"full_name":"Testa Salmazo, Anita P","first_name":"Anita P","last_name":"Testa Salmazo","id":"41F1F098-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Luciano","full_name":"Ciccarelli, Luciano","last_name":"Ciccarelli"},{"full_name":"Puchinger, Martin","first_name":"Martin","last_name":"Puchinger"},{"full_name":"Gkougkoulia, Eirini A.","first_name":"Eirini A.","last_name":"Gkougkoulia"},{"full_name":"Ribeiro, Euripedes de Almeida","first_name":"Euripedes de Almeida","last_name":"Ribeiro"},{"last_name":"Marlovits","full_name":"Marlovits, Thomas C.","first_name":"Thomas C."},{"full_name":"Bhattacharya, Alok","first_name":"Alok","last_name":"Bhattacharya"},{"first_name":"Kristina","full_name":"Djinovic-Carugo, Kristina","last_name":"Djinovic-Carugo"}],"page":"22101-22112","citation":{"short":"N. Pinotsis, K. Zielinska, M. Babuta, J.L. Arolas, J. Kostan, M.B. Khan, C. Schreiner, A.P. Testa Salmazo, L. Ciccarelli, M. Puchinger, E.A. Gkougkoulia, E. de A. Ribeiro, T.C. Marlovits, A. Bhattacharya, K. Djinovic-Carugo, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 22101–22112.","ieee":"N. Pinotsis <i>et al.</i>, “Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 117, no. 36. National Academy of Sciences, pp. 22101–22112, 2020.","apa":"Pinotsis, N., Zielinska, K., Babuta, M., Arolas, J. L., Kostan, J., Khan, M. B., … Djinovic-Carugo, K. (2020). Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.1917269117\">https://doi.org/10.1073/pnas.1917269117</a>","chicago":"Pinotsis, Nikos, Karolina Zielinska, Mrigya Babuta, Joan L. Arolas, Julius Kostan, Muhammad Bashir Khan, Claudia Schreiner, et al. “Calcium Modulates the Domain Flexibility and Function of an α-Actinin Similar to the Ancestral α-Actinin.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.1917269117\">https://doi.org/10.1073/pnas.1917269117</a>.","ama":"Pinotsis N, Zielinska K, Babuta M, et al. Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2020;117(36):22101-22112. doi:<a href=\"https://doi.org/10.1073/pnas.1917269117\">10.1073/pnas.1917269117</a>","ista":"Pinotsis N, Zielinska K, Babuta M, Arolas JL, Kostan J, Khan MB, Schreiner C, Testa Salmazo AP, Ciccarelli L, Puchinger M, Gkougkoulia EA, Ribeiro E de A, Marlovits TC, Bhattacharya A, Djinovic-Carugo K. 2020. Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. Proceedings of the National Academy of Sciences of the United States of America. 117(36), 22101–22112.","mla":"Pinotsis, Nikos, et al. “Calcium Modulates the Domain Flexibility and Function of an α-Actinin Similar to the Ancestral α-Actinin.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 117, no. 36, National Academy of Sciences, 2020, pp. 22101–12, doi:<a href=\"https://doi.org/10.1073/pnas.1917269117\">10.1073/pnas.1917269117</a>."},"quality_controlled":"1","publisher":"National Academy of Sciences","status":"public","acknowledged_ssus":[{"_id":"LifeSc"}],"ddc":["570"],"day":"08","date_created":"2024-03-04T10:03:52Z","language":[{"iso":"eng"}],"oa_version":"Published Version","_id":"15061","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","fulldoi":"https://doi.org/10.1073/pnas.1917269117","volume":117,"publication_status":"published","oa":1}]