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Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy.

ABSTRACT: Transcription is often the first biosynthetic event of viral infection. Viruses produce preferentially viral transcriptional regulators (vTRs) essential for expressing viral genes and regulating essential host cell proteins to enable viral genome replication. As vTRs are unique viral proteins that promote the transcription of viral nucleic acid, vTRs interact with host proteins to suppress detection and immune reactions to viral infection. Thus, vTRs are promising therapeutic targets that are sequentially and structurally distinct from host cell proteins. Here, we review vTRs of three human oncoviruses: HBx of hepatitis B virus, HBZ of human T-lymphotropic virus type 1, and Rta of Epstein-Barr virus. We present three cunningly exciting and dangerous transcription strategies that make viral infections so efficient. We use available structural and functional knowledge to critically examine the potential of vTRs as new antiviral-anticancer therapy targets. For each oncovirus, we describe (i) the strategy of viral genome transcription; (ii) vTRs' structure and binding partners essential for transcription regulation; and (iii) advantages and challenges of vTR targeting in antiviral therapies. We discuss the implications of vTR regulation for oncogenesis and perspectives on developing novel antiviral and anticancer strategies.

SUBMITTER: Necasova I

PROVIDER: S-EPMC8892037 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy.

Nečasová Ivona I Stojaspal Martin M Motyčáková Edita E Brom Tomáš T Janovič Tomáš T Hofr Ctirad C

NAR cancer 20220303 1

Transcription is often the first biosynthetic event of viral infection. Viruses produce preferentially viral transcriptional regulators (vTRs) essential for expressing viral genes and regulating essential host cell proteins to enable viral genome replication. As vTRs are unique viral proteins that promote the transcription of viral nucleic acid, vTRs interact with host proteins to suppress detection and immune reactions to viral infection. Thus, vTRs are promising therapeutic targets that are se ...[more]

PMID: 35252867

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Project description:One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model. Given a high-dimensional transcriptional profiling dataset from human blood leukocytes, an elementary set of temporal dynamic responses which capture the essence of a pro-inflammatory phase, a counter-regulatory response and a dysregulation in leukocyte bioenergetics has been extracted. Upon identification of these expression patterns, fourteen inflammation-specific gene batteries that represent groups of hypothetically 'coregulated' genes are proposed. Subsequently, statistically significant cis-regulatory modules (CRMs) are identified and decomposed into a list of critical transcription factors (34) that are validated largely on primary literature. Finally, our analysis further allows for the construction of a dynamic representation of the temporal transcriptional regulatory program across the host, deciphering possible combinatorial interactions among factors under which they might be active. Although much remains to be explored, this study has computationally identified key transcription factors and proposed a putative time-dependent transcriptional regulatory program associated with critical transcriptional inflammatory responses. These results provide a solid foundation for future investigations to elucidate the underlying transcriptional regulatory mechanisms under the host inflammatory response. Also, the assumption that coexpressed genes that are functionally relevant are more likely to share some common transcriptional regulatory mechanism seems to be promising, making the proposed framework become essential in unravelling context-specific transcriptional regulatory interactions underlying diverse mammalian biological processes.

Project description:Accumulation of compatible solutes is a common stress response of microorganisms challenged by high osmolarity; it can be achieved either through synthesis or import. These processes have been intensively studied in Bacillus subtilis, where systems for the production of the compatible solutes proline and glycine betaine have been identified, and in which five transporters for osmostress protectants (Opu) have been characterized. Glycine betaine synthesis relies on the import of choline via the substrate-restricted OpuB system and the promiscuous OpuC transporter and its subsequent oxidation by the GbsAB enzymes. Transcription of the opuB and gbsAB operons is under control of the MarR-type regulator GbsR, which acts as an intracellular choline-responsive repressor. Modeling studies using the X-ray structure of the Mj223 protein from Methanocaldococcus jannaschii as the template suggest that GbsR is a homo-dimer with an N-terminal DNA-reading head and C-terminal dimerization domain; a flexible linker connects these two domains. In the vicinity of the linker region, an aromatic cage is predicted as the inducer-binding site, whose envisioned architecture resembles that present in choline and glycine betaine substrate-binding proteins of ABC transporters. We used bioinformatics to assess the phylogenomics of GbsR-type proteins and found that they are widely distributed among Bacteria and Archaea. Alignments of GbsR proteins and analysis of the genetic context of the corresponding structural genes allowed their assignment into four sub-groups. In one of these sub-groups of GbsR-type proteins, gbsR-type genes are associated either with OpuA-, OpuB-, or OpuC-type osmostress protectants uptake systems. We focus here on GbsR-type proteins, named OpuAR by us, that control the expression of opuA-type gene clusters. Using such a system from the marine bacterium Bacillus infantis, we show that OpuAR acts as a repressor of opuA transcription, where several compatible solutes (e.g., choline, glycine betaine, proline betaine) serve as its inducers. Site-directed mutagenesis studies allowed a rational improvement of the putative inducer-binding site in OpuAR with respect to the affinity of choline and glycine betaine binding. Collectively, our data characterize GbsR-/OpuAR-type proteins as an extended sub-group within the MarR-superfamily of transcriptional regulators and identify a novel type of substrate-inducible import system for osmostress protectants.

Dataset Information

Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy.

Publications

Transcriptional regulators of human oncoviruses: structural and functional implications for anticancer therapy.

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