Herpesviruses mimic zygotic genome activation to promote viral replication
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ABSTRACT:
PROVIDER: PRJNA981526 | ENA |
REPOSITORIES: ENA
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Project description:DUX4 is a germline transcription factor and a master regulator of zygotic genome activation. During early embryogenesis, DUX4 is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is silenced and its activation in adult muscle cells causes the genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). Here we show that herpesviruses actively induce DUX4 expression to promote viral transcription and replication. We demonstrate that HSV-1 immediate early proteins directly induce expression of DUX4 and its target genes including endogenous retroelements, which mimics zygotic genome activation. DUX4 directly binds to the viral genome, promotes viral transcription and genetic depletion of DUX4 by CRISPR/Cas9 abrogates viral replication. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. Herpesviruses activate DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
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2018-10-11 | GSE96531 | GEO
Project description:The human gamma herpesvirus Epstein-Barr virus, infects most adults and is an important contributor to the development of many types of cancer. Essential contributions of viral genes to replication are known but the potential contributions of cell genes to viral replication are less well delineated. A key player is the viral protein Zta (BZLF1, ZEBRA, Z). This sequence-specific DNA-binding protein can disrupt viral latency by driving the transcription of target genes and by interacting with the EBV lytic origin of replication. Here we used an unbiased approach to identify the Zta-interactome in cells derived from a Burkitt’s lymphoma. Isolating Zta and associated proteins from Burkitt’s lymphoma cells undergoing EBV replication, followed by Tandem Mass Tag (TMT) mass spectrometry resulted in the identification of forty-four viral and cellular proteins in the Zta interactome. Of these two were known targets of Zta. The association of Zta with Hsc70 and the contribution that Hsc70 plays to EBV replication mirrors a contribution from HSP70 family members to the replication of other herpesviruses. Conversely, the association of Zta with NFATc2 has no known parallels for other herpesviruses. Zta attenuates the activity of an NFAT-dependent promoter, which shows a potential for dampening the expression of genes regulated by calcium-dependent signal transduction. Indeed, Zta has the ability to affect a feed-back loop limiting its own expression, which would aid viral replication by preventing the toxic effects of Zta overexpression.
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Project description:DNA methylation is an essential epigenetic mark in mammals, and its pattern has to be re-established after each round of DNA replication. The protein UHRF1 is known to be necessary for this process, but its mode of action is unclear. Using proteomics, we havefound that a replication factor, DNA Ligase 1 (LIG1), is a direct interactor of UHRF1. The interaction is mediated bythe Tudor domain of UHRF1 and an H3K9-like histone mimic within LIG1. This mimic ismethylated on a conserved lysine by the enzymes G9a and GLP, and outcompetes H3K9me3 for UHRF1 binding. Lastly, the interaction with LIG1 promotes the recruitment of UHRF1 to sites of DNA replication and is required for DNA methylation maintenance. These results clarify UHRF1 activity, identify a new non-histone target of G9a and GLP, and provide the first example of a histone mimic that coordinates DNA replication and DNA remethylation
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Project description:Regulation of DNA replication and copy number are necessary to promote genome stability and maintain cell and tissue function. DNA replication is regulated temporally in a process known as replication timing (RT). Rif1 is key regulator of RT and has a critical function in copy number control in polyploid cells. In a previous study (Munden et al., 2018), we demonstrated that Rif1 functions with SUUR to inhibit replication fork progression and promote underreplication of specific genomic regions. How Rif1-dependent control of RT factors into its ability to promote underreplication is unknown. By applying a computational approach to measure RT in Drosophila polyploid cells, we show that SUUR and Rif1 have differential roles in controlling underreplication and RT. Our findings reveal that Rif1 functions both upstream and downstream of SUUR to promote underreplication. Our work provides new mechanistic insight into the process of underreplication and its links to RT.
2021-09-02 | GSE172375 | GEO
Project description:SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cell’s ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.
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Project description:FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress
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Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. Here, we report that upon replication stress, phosphorylation of the FANCD2 N-terminus by CHK1 triggers FBXL12-dependent proteasomal degradation of FANCD2, facilitating clearance of FANCD2 at stalled replication forks. This mechanism is required to promote efficient and faithful DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Notably, reconstitution of FANCD2 with mutations in the N-terminal phosphodegron fail to re-establish fork progression in FANCD2-deficient human fibroblasts in response to replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, CYCLIN E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification of FBXL12 is linked to reduced survival in patients with high CYCLIN E expressing breast tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability of CYCLIN E-overexpressing cancer cells and may represent a novel target for cancer therapy.
2023-08-16 | GSE232558 | GEO