The Interactive Complex between Cytomegalovirus Kinase vCDK/pUL97 and Host Factors CDK7-Cyclin H Determines Individual Patterns of Transcription in Infected Cells

• Published in: International journal of molecular sciences Vol. 24; no. 24; p. 17421
• Main Authors: Schütz, Martin, Cordsmeier, Arne, Wangen, Christina, Horn, Anselm H C, Wyler, Emanuel, Ensser, Armin, Sticht, Heinrich, Marschall, Manfred
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.12.2023
• Subjects: Cell cycle; Cyclin H - metabolism; Cyclin-dependent kinases; cyclin-dependent kinases (CDKs); Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Cyclins - metabolism; Cytomegalovirus; Cytomegalovirus - genetics; functional complexation with host CDK7; Gene expression; Herpesviridae Infections; human cytomegalovirus; Humans; impact on RNA polymerase (RNAP II) in infected cells; Infections; Kinases; Metabolism; Ontology; Pathogenesis; Phosphorylation; RNA polymerase; vCDK/pUL97–cyclin binding; viral CDK ortholog (vCDK/pUL97); cyclin-dependent kinases (CDKs); first vCDK/pUL97-specific transcriptomic analysis; impact on RNA polymerase (RNAP II) in infected cells; viral CDK ortholog (vCDK/pUL97); functional complexation with host CDK7; human cytomegalovirus; vCDK/pUL97–cyclin binding
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242417421

The infection of human cytomegalovirus (HCMV) is strongly determined by the host-cell 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-host 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-cyclin H-CDK7 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.