{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:38Z","timestamp":1788544178354,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T00:00:00Z","timestamp":1702425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["A88"],"award-info":[{"award-number":["A88"]}]},{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["AZ2022.073.1"],"award-info":[{"award-number":["AZ2022.073.1"]}]},{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["DeeP-CMV\/AP-5"],"award-info":[{"award-number":["DeeP-CMV\/AP-5"]}]},{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["2015-16"],"award-info":[{"award-number":["2015-16"]}]},{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["2017-18"],"award-info":[{"award-number":["2017-18"]}]},{"name":"Interdisciplinary Center of Clinical Research of the Medical Center\/Universit\u00e4tsklinikum Erlangen","award":["2020-21"],"award-info":[{"award-number":["2020-21"]}]},{"name":"Wilhelm Sander-Stiftung","award":["A88"],"award-info":[{"award-number":["A88"]}]},{"name":"Wilhelm Sander-Stiftung","award":["AZ2022.073.1"],"award-info":[{"award-number":["AZ2022.073.1"]}]},{"name":"Wilhelm Sander-Stiftung","award":["DeeP-CMV\/AP-5"],"award-info":[{"award-number":["DeeP-CMV\/AP-5"]}]},{"name":"Wilhelm Sander-Stiftung","award":["2015-16"],"award-info":[{"award-number":["2015-16"]}]},{"name":"Wilhelm Sander-Stiftung","award":["2017-18"],"award-info":[{"award-number":["2017-18"]}]},{"name":"Wilhelm Sander-Stiftung","award":["2020-21"],"award-info":[{"award-number":["2020-21"]}]},{"name":"Bayerische Forschungsstiftung","award":["A88"],"award-info":[{"award-number":["A88"]}]},{"name":"Bayerische Forschungsstiftung","award":["AZ2022.073.1"],"award-info":[{"award-number":["AZ2022.073.1"]}]},{"name":"Bayerische Forschungsstiftung","award":["DeeP-CMV\/AP-5"],"award-info":[{"award-number":["DeeP-CMV\/AP-5"]}]},{"name":"Bayerische Forschungsstiftung","award":["2015-16"],"award-info":[{"award-number":["2015-16"]}]},{"name":"Bayerische Forschungsstiftung","award":["2017-18"],"award-info":[{"award-number":["2017-18"]}]},{"name":"Bayerische Forschungsstiftung","award":["2020-21"],"award-info":[{"award-number":["2020-21"]}]},{"name":"DAAD-Go8","award":["A88"],"award-info":[{"award-number":["A88"]}]},{"name":"DAAD-Go8","award":["AZ2022.073.1"],"award-info":[{"award-number":["AZ2022.073.1"]}]},{"name":"DAAD-Go8","award":["DeeP-CMV\/AP-5"],"award-info":[{"award-number":["DeeP-CMV\/AP-5"]}]},{"name":"DAAD-Go8","award":["2015-16"],"award-info":[{"award-number":["2015-16"]}]},{"name":"DAAD-Go8","award":["2017-18"],"award-info":[{"award-number":["2017-18"]}]},{"name":"DAAD-Go8","award":["2020-21"],"award-info":[{"award-number":["2020-21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The infection of human cytomegalovirus (HCMV) is strongly determined by the host\u2013cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as cyclin-dependent kinases (CDKs) and the viral CDK ortholog (vCDK\/pUL97), play an important role in both viral reproduction and virus\u2013host interaction. Very recently, we reported on the complexes formed between vCDK\/pUL97, human cyclin H, and CDK7. Major hallmarks of this interplay are the interaction between cyclin H and vCDK\/pUL97, which is consistently detectable across various conditions and host cell types of infection, the decrease or increase in pUL97 kinase activity resulting from cyclin H knock-down or elevated levels, respectively, and significant trans-stimulation of human CDK7 activity by pUL97 in vitro. Due to the fact that even a ternary complex of vCDK\/pUL97\u2013cyclin H\u2013CDK7 can be detected by coimmunoprecipitation and visualized by bioinformatic structural modeling, we postulated a putative impact of the respective kinase activities on the patterns of transcription in HCMV-infected cells. Here, we undertook a first vCDK\/pUL97-specific transcriptomic analysis, which combined conditions of fully lytic HCMV replication with those under specific vCDK\/pUL97 or CDK7 drug-mediated inhibition or transient cyclin H knockout. The novel results were further strengthened using bioinformatic modeling of the involved multi-protein complexes. Our data underline the importance of these kinase activities for the C-terminal domain (CTD) phosphorylation-driven activation of host RNA polymerase in HCMV-infected cells. The impact of the individual experimental conditions on differentially expressed gene profiles is described in detail and discussed.<\/jats:p>","DOI":"10.3390\/ijms242417421","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T04:14:42Z","timestamp":1702440882000},"page":"17421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Interactive Complex between Cytomegalovirus Kinase vCDK\/pUL97 and Host Factors CDK7\u2013Cyclin H Determines Individual Patterns of Transcription in Infected Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Martin","family":"Sch\u00fctz","sequence":"first","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Cordsmeier","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Wangen","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-8103","authenticated-orcid":false,"given":"Anselm H. C.","family":"Horn","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel","family":"Wyler","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC), 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8873-3863","authenticated-orcid":false,"given":"Armin","family":"Ensser","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-045X","authenticated-orcid":false,"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Marschall","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1182\/blood-2002-03-0993","article-title":"Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: Importance of viral load and T-cell immunity","volume":"101","author":"Boeckh","year":"2003","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1743-422X-5-47","article-title":"Severe cytomegalovirus infection in apparently immunocompetent patients: A systematic review","volume":"5","author":"Rafailidis","year":"2008","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1111\/j.1469-0691.2007.01781.x","article-title":"Clinical relevance of cytomegalovirus infection in patients with disorders of the immune system","volume":"13","author":"Steininger","year":"2007","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/1521654031000070645","article-title":"Herpes virus replication","volume":"55","author":"Boehmer","year":"2003","journal-title":"IUBMB Life"},{"key":"ref_5","unstructured":"Goodrum, F., Britt, W., and Mocarski, E.S. (2021). Fields Virology: DNA Viruses, LWW. [7th ed.]."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gugliesi, F., Coscia, A., Griffante, G., Galitska, G., Pasquero, S., Albano, C., and Biolatti, M. (2020). Where do we Stand after Decades of Studying Human Cytomegalovirus?. Microorganisms, 8.","DOI":"10.3390\/microorganisms8050685"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1128\/CMR.15.4.680-715.2002","article-title":"Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant","volume":"15","author":"Revello","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1741-4520.2009.00222.x","article-title":"Effects of cytomegalovirus infection on embryogenesis and brain development","volume":"49","author":"Tsutsui","year":"2009","journal-title":"Congenit. Anom."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Njue, A., Coyne, C., Margulis, A.V., Wang, D., Marks, M.A., Russell, K., Das, R., and Sinha, A. (2020). The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms. Viruses, 13.","DOI":"10.3390\/v13010020"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sch\u00fctz, M., Steingruber, M., Socher, E., M\u00fcller, R., Wagner, S., K\u00f6gel, M., Sticht, H., and Marschall, M. (2021). Functional Relevance of the Interaction between Human Cyclins and the Cytomegalovirus-Encoded CDK-Like Protein Kinase pUL97. Viruses, 13.","DOI":"10.3390\/v13071248"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sch\u00fctz, M., M\u00fcller, R., Socher, E., Wangen, C., Full, F., Wyler, E., Wong, D., Scherer, M., Stamminger, T., and Chou, S. (2022). Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H. Int. J. Mol. Sci., 23.","DOI":"10.21203\/rs.3.rs-1676959\/v1"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.coviro.2021.11.016","article-title":"Virus-host protein interactions as footprints of human cytomegalovirus replication","volume":"52","author":"Tyl","year":"2022","journal-title":"Curr. Opin. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"572","DOI":"10.4161\/cc.4.4.1607","article-title":"CAK-Cyclin-dependent Activating Kinase: A key kinase in cell cycle control and a target for drugs?","volume":"4","author":"Lolli","year":"2005","journal-title":"Cell Cycle"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Malumbres, M. (2014). Cyclin-dependent kinases. Genome Biol., 15.","DOI":"10.1186\/gb4184"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.semcdb.2020.03.009","article-title":"Mammalian cell cycle cyclins","volume":"107","author":"Malumbres","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s10555-020-09885-8","article-title":"CDK7 inhibitors as anticancer drugs","volume":"39","author":"Sava","year":"2020","journal-title":"Cancer Metastasis Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1126\/science.1152095","article-title":"Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function","volume":"320","author":"Hume","year":"2008","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6583","DOI":"10.1074\/jbc.M116.773150","article-title":"Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins","volume":"292","author":"Iwahori","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.virol.2004.03.015","article-title":"Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase","volume":"324","author":"Baek","year":"2004","journal-title":"Virology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kuny, C.V., Chinchilla, K., Culbertson, M.R., and Kalejta, R.F. (2010). Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001092"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6188","DOI":"10.1074\/jbc.RA118.007049","article-title":"Cyclins B1, T1, and H differ in their molecular mode of interaction with cytomegalovirus protein kinase pUL97","volume":"294","author":"Steingruber","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"199200","DOI":"10.1016\/j.virusres.2023.199200","article-title":"Cytomegalovirus cyclin-dependent kinase ortholog vCDK\/pUL97 undergoes regulatory interaction with human cyclin H and CDK7 to codetermine viral replication efficiency","volume":"335","author":"Wangen","year":"2023","journal-title":"Virus Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wild, M., Hahn, F., Br\u00fcckner, N., Sch\u00fctz, M., Wangen, C., Wagner, S., Sommerer, M., Strobl, S., and Marschall, M. (2022). Cyclin-Dependent Kinases (CDKs) and the Human Cytomegalovirus-Encoded CDK Ortholog pUL97 Represent Highly Attractive Targets for Synergistic Drug Combinations. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052493"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"iyad031","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Aleksander","year":"2023","journal-title":"Genetics"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hertel, L., Chou, S., and Mocarski, E.S. (2007). Viral and cell cycle\u2013regulated kinases in cytomegalovirus-induced pseudomitosis and replication. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030006"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ball, C.B., Parida, M., Li, M., Spector, B.M., Suarez, G.A., Meier, J.L., and Price, D.H. (2022). Human Cytomegalovirus Infection Elicits Global Changes in Host Transcription by RNA Polymerases I, II, and III. Viruses, 14.","DOI":"10.3390\/v14040779"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s00430-015-0396-z","article-title":"Human cytomegalovirus riding the cell cycle","volume":"204","author":"Spector","year":"2015","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2107406119","DOI":"10.1073\/pnas.2107406119","article-title":"BEND3 safeguards pluripotency by repressing differentiation-associated genes","volume":"119","author":"Kurniawan","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6359","DOI":"10.1128\/JVI.03477-12","article-title":"The ULb\u2019 region of the human cytomegalovirus genome confers an increased requirement for the viral protein kinase UL97","volume":"87","author":"Wang","year":"2013","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1128\/JVI.01681-07","article-title":"Inhibition of the cyclin-dependent kinases at the beginning of human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome","volume":"82","author":"Kapasi","year":"2008","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15477","DOI":"10.1128\/JVI.79.24.15477-15493.2005","article-title":"Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7","volume":"79","author":"Tamrakar","year":"2005","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1038\/s41467-022-29739-x","article-title":"Differences in RNA polymerase II complexes and their interactions with surrounding chromatin on human and cytomegalovirus genomes","volume":"13","author":"Spector","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eaba8490","DOI":"10.1126\/science.aba8490","article-title":"Structural insights into preinitiation complex assembly on core promoters","volume":"372","author":"Chen","year":"2021","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. 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