Human herpesvirus-6B protein U19 contains a p53 BOX I homology motif for HDM2 binding and p53 stabilization

Kofod-Olsen, Emil; Pettersson, Susanne; Wallace, Maura; Abduljabar, Ahmed B.; Øster, Bodil; Hupp, Ted R.; Höllsberg, Per

doi:10.1016/j.virol.2013.10.002

Cited by 2 publications

(2 citation statements)

References 36 publications

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“…Intriguingly, using the Rad51 RI-1 inhibitor (27), Wallaschek et al recently reported that the Rad51 recombinase is dispensable for HHV-6A and HHV-6B integration in U2OS cells (14). Our results also suggest that abrogation of the p53 protein, which is involved in DNA repair mechanisms and interacts with the HHV-6 U14 and U19 proteins (28,29), does not affect HHV-6 chromosomal integration. Thus, our results indicate that HHV-6 U94 and the cellular p53 and Rad51 proteins are dispensable for HHV-6 integration, suggesting that other viral or cellular recombinases can complement their functions.…”

Section: Discussionsupporting

confidence: 58%

Cell Culture Systems To Study Human Herpesvirus 6A/B Chromosomal Integration

Gravel¹,

Dubuc²,

Wallaschek

et al. 2017

J Virol

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Human herpesviruses 6A/B (HHV-6A/B) can integrate their viral genomes in the telomeres of human chromosomes. The viral and cellular factors contributing to HHV-6A/B integration remain largely unknown, mostly due to the lack of efficient and reproducible cell culture models to study HHV-6A/B integration. In this study, we characterized the HHV-6A/B integration efficiencies in several human cell lines using two different approaches. First, after a short-term infection (5 h), cells were processed for single-cell cloning and analyzed for chromosomally integrated HHV-6A/B (ciHHV-6A/B). Second, cells were infected with HHV-6A/B and allowed to grow in bulk for 4 weeks or longer and then analyzed for the presence of ciHHV-6. Using quantitative PCR (qPCR), droplet digital PCR, and fluorescent in situ hybridization, we could demonstrate that HHV-6A/B integrated in most human cell lines tested, including telomerase-positive (HeLa, MCF-7, HCT-116, and HEK293T) and telomerase-negative cell lines (U2OS and GM847). Our results also indicate that inhibition of DNA replication, using phosphonoacetic acid, did not affect HHV-6A/B integration. Certain clones harboring ciHHV-6A/B spontaneously express viral genes and proteins. Treatment of cells with phorbol ester or histone deacetylase inhibitors triggered the expression of many viral genes, including U39, U90, and U100, without the production of infectious virus, suggesting that the tested stimuli were not sufficient to trigger full reactivation. In summary, both integration models yielded comparable results and should enable the identification of viral and cellular factors contributing to HHV-6A/B integration and the screening of drugs influencing viral gene expression, as well as the release of infectious HHV-6A/B from the integrated state.IMPORTANCE The analysis and understanding of HHV-6A/B genome integration into host DNA is currently limited due to the lack of reproducible and efficient viral integration systems. In the present study, we describe two quantitative cell culture viral integration systems. These systems can be used to define cellular and viral factors that play a role in HHV-6A/B integration. Furthermore, these systems will allow us to decipher the conditions resulting in virus gene expression and excision of the integrated viral genome resulting in reactivation.KEYWORDS chromosomal integration, ddPCR, telomere

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Section: Discussionsupporting

confidence: 58%

Cell Culture Systems To Study Human Herpesvirus 6A/B Chromosomal Integration

Gravel¹,

Dubuc²,

Wallaschek

et al. 2017

J Virol

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“…The roles of many HHV-6 genes are poorly understood but like other herpesviruses, HHV-6 is able to circumvent the pathway that results in p53 mediated cell cycle arrest and so is able to replicate 12 . Several HHV-6 genes, including DR6/DR7 (ORF-1), U14 and U19, encode proteins that interact with p53 directly of indirectly 13 14 15 16 . Interestingly the U14 protein has been detected with p53 in virions and its role is under intense investigation 14 17 18 .…”

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confidence: 99%

HHV-8-unrelated primary effusion-like lymphoma associated with clonal loss of inherited chromosomally-integrated human herpesvirus-6A from the telomere of chromosome 19q

Zhang

Cotton

Hidalgo‐Bravo

et al. 2016

Sci Rep

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Primary effusion lymphomas (PEL) are associated with human herpesvirus-8 (HHV-8) and usually occur in immunocompromised individuals. However, there are numerous reports of HHV-8-unrelated PEL-like lymphomas with unknown aetiology. Here we characterize an HHV-8-unrelated PEL-like lymphoma in an elderly woman who was negative for human immunodeficiency viruses 1 and 2, and hepatitis B and C. The woman was, however, a carrier of an inherited-chromosomally-integrated human herpesvirus-6A (iciHHV-6A) genome in one 19q telomere. The iciHHV-6A genome was complete in blood DNA, encoding a full set of protein-coding genes. Interestingly, the entire iciHHV-6A genome was absent from the HHV-8-unrelated-PEL-like lymphoma cells despite retention of both copies of chromosome 19. The somatic loss of the 19q-iciHHV-6A genome occurred very early during lymphoma development and we propose it occurred via telomere-loop formation and excision to release a circular viral genome that was subsequently lost. Whether release of the HHV-6A genome from the telomere contributed to lymphomagenesis, or was coincidental, remains unclear but this event may have deregulated the expression of HHV-6A or 19q genes or else disrupted telomere function. To establish the frequency and importance of iciHHV-6 loss from telomeres, the HHV-6 copy number should be assessed in tumours that arise in iciHHV-6 carriers.

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Human herpesvirus-6B protein U19 contains a p53 BOX I homology motif for HDM2 binding and p53 stabilization

Cited by 2 publications

References 36 publications

Cell Culture Systems To Study Human Herpesvirus 6A/B Chromosomal Integration

Cell Culture Systems To Study Human Herpesvirus 6A/B Chromosomal Integration

HHV-8-unrelated primary effusion-like lymphoma associated with clonal loss of inherited chromosomally-integrated human herpesvirus-6A from the telomere of chromosome 19q

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