Search results for " REPLICATION"

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

2015

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex migh…

ICTV Virus Taxonomy Profile: Metaviridae

2020

Metaviridae is a family of retrotransposons and reverse-transcribing viruses with long terminal repeats belonging to the order Ortervirales. Members of the genera Errantivirus and Metavirus include, respectively, Saccharomyces cerevisiae Ty3 virus and its Gypsy-like relatives in drosophilids. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Metaviridae, which is available at ictv.global/report/metaviridae.

Artemisinin Derivatives Target Topoisomerase 1 and Cause DNA Damage in Silico and in Vitro

2017

DNA topoisomerases 1 and 2 are enzymes that maintain DNA topology and play important essential genome functions, including DNA replication and transcription. Aberrant topoisomerases cause genome instability and a wide range of diseases, cancer in particular. Both Topo 1 and 2 are the targets of valuable anticancer drugs, such as camptothecin. It has been previously shown that artemisinin, a sesquiterpene lactone from Artemisia annua L. also known as qinghaosu, possesses anti-cancer effects and one of its derivatives, artesunate inhibits Topo 2. In this study, we evaluated artemisinin and 40 derivatives as potential Topo 1 inhibitors at first by in silico molecular docking analyses. Five com…

A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development.

2017

Summary Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apop…

Hepatitis B Virus Subverts the Autophagy Elongation Complex Atg5-12/16L1 and Does Not Require Atg8/LC3 Lipidation for Viral Maturation

2018

ABSTRACT Previous studies indicated that hepatitis B virus (HBV) stimulates autophagy to favor its production. To understand how HBV co-opts autophagy as a proviral machinery, we studied the roles of key autophagy proteins in HBV-replicating liver cell cultures. RNA interference-mediated silencing of Atg5, Atg12, and Atg16L1, which promote autophagophore expansion and LC3 membrane conjugation, interfered with viral core/nucleocapsid (NC) formation/stability and strongly diminished virus yields. Concomitantly, the core/NC membrane association and their sorting to envelope-positive compartments were perturbed. A close inspection of the HBV/autophagy cross talk revealed that the virus depended…

APOBEC3-mediated restriction of RNA virus replication

2018

AbstractAPOBEC3 family members are cytidine deaminases with roles in intrinsic responses to infection by retroviruses and retrotransposons, and in the control of other DNA viruses, such as herpesviruses, parvoviruses and hepatitis B virus. Although effects of APOBEC3 members on viral DNA have been demonstrated, it is not known whether they edit RNA genomes through cytidine deamination. Here, we investigated APOBEC3-mediated restriction of Coronaviridae. In experiments in vitro, three human APOBEC3 proteins (A3C, A3F and A3H) inhibited HCoV-NL63 infection and limited production of progeny virus, but did not cause hypermutation of the coronaviral genome. APOBEC3-mediated restriction was parti…

2016

The human cytomegalovirus (HCMV) replicates to high titers in primary human fibroblast cell cultures. A variety of primary human cells and some tumor-derived cell lines do also support permissive HCMV replication, yet at low levels. Cell lines established by transfection of the transforming functions of adenoviruses have been notoriously resistant to HCMV replication and progeny production. Here, we provide first-time evidence that a permanent cell line immortalized by adenovirus type 5 E1A and E1B (CAP) is supporting the full HCMV replication cycle and is releasing infectious progeny. The CAP cell line had previously been established from amniotic fluid cells which were likely derived from…

Efficient Delivery of Human Cytomegalovirus T Cell Antigens by Attenuated Sendai Virus Vectors.

2018

ABSTRACT Human cytomegalovirus (HCMV) represents a major cause of clinical complications during pregnancy as well as immunosuppression, and the licensing of a protective HCMV vaccine remains an unmet global need. Here, we designed and validated novel Sendai virus (SeV) vectors delivering the T cell immunogens IE-1 and pp65. To enhance vector safety, we used a replication-deficient strain (rdSeV) that infects target cells in a nonproductive manner while retaining viral gene expression. In this study, we explored the impact that transduction with rdSeV has on human dendritic cells (DCs) by comparing it to the parental, replication-competent Sendai virus strain (rcSeV) as well as the poxvirus …

Regulatory Interaction between the Cellular Restriction Factor IFI16 and Viral pp65 (pUL83) Modulates Viral Gene Expression and IFI16 Protein Stabili…

2016

ABSTRACT A key player in the intrinsic resistance against human cytomegalovirus (HCMV) is the interferon-γ-inducible protein 16 (IFI16), which behaves as a viral DNA sensor in the first hours postinfection and as a repressor of viral gene transcription in the later stages. Previous studies on HCMV replication demonstrated that IFI16 binds to the viral protein kinase pUL97, undergoes phosphorylation, and relocalizes to the cytoplasm of infected cells. In this study, we demonstrate that the tegument protein pp65 (pUL83) recruits IFI16 to the promoter of the UL54 gene and downregulates viral replication, as shown by use of the HCMV mutant v65Stop, which lacks pp65 expression. Interestingly, at…

Dynamic regulatory interaction between cytomegalovirus major tegument protein pp65 and protein kinase pUL97 in intracellular compartments, dense bodi…

2017

Human cytomegalovirus (HCMV) is a ubiquitous pathogen of considerable clinical importance. Understanding the processes that are important for viral replication is essential for the development of therapeutic strategies against HCMV infection. The HCMV-encoded protein kinase pUL97 is an important multifunctional regulator of viral replication. Several viral and cellular proteins are phosphorylated by pUL97. The phosphoprotein pp65 is one important substrate of pUL97. It is the most abundant tegument protein of HCMV virions, mediating the upload of other virion constituents and contributing to particle integrity. Further to that, it interferes with host innate immune defences, thereby enablin…