Viral Proteins U41 and U70 of Human Herpesvirus 6A Are Dispensable for Telomere Integration

Wight, Darren J.; Wallaschek, Nina; Sanyal, Anirban; Weller, Sandra; Flamand, Louis; Kaufer, Benedikt B.

doi:10.3390/v10110656

Cited by 17 publications

(28 citation statements)

References 35 publications

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“…This data is consistent with previous data on the orthologues of HSV-1 that showed UL12 aids in DNA repair via the SSA pathway [17]. By contrast, UL29 did not aid in SSA repair or augment the effect of UL12 (Figure 3), which is also consistent with recently published data on HHV-6A [29].…”

Section: Discussionsupporting

confidence: 93%

The Role of Marek’s Disease Virus UL12 and UL29 in DNA Recombination and the Virus Lifecycle

Previdelli

Bertzbach

Wight

et al. 2019

Viruses

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Marek’s disease virus (MDV) is an oncogenic alphaherpesvirus that infects chickens and integrates its genome into the telomeres of latently infected cells. MDV encodes two proteins, UL12 and UL29 (ICP8), that are conserved among herpesviruses and could facilitate virus integration. The orthologues of UL12 and UL29 in herpes simplex virus 1 (HSV-1) possess exonuclease and single strand DNA-binding activity, respectively, and facilitate DNA recombination; however, the role of both proteins in the MDV lifecycle remains elusive. To determine if UL12 and/or UL29 are involved in virus replication, we abrogated their expression in the very virulent RB-1B strain. Abrogation of either UL12 or UL29 resulted in a severe impairment of virus replication. We also demonstrated that MDV UL12 can aid in single strand annealing DNA repair, using a well-established reporter cell line. Finally, we assessed the role of UL12 and UL29 in MDV integration and maintenance of the latent virus genome. We could demonstrate that knockdown of UL12 and UL29 does not interfere with the establishment or maintenance of latency. Our data therefore shed light on the role of MDV UL12 and UL29 in MDV replication, DNA repair, and maintenance of the latent virus genome.

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Section: Discussionsupporting

confidence: 93%

The Role of Marek’s Disease Virus UL12 and UL29 in DNA Recombination and the Virus Lifecycle

Previdelli

Bertzbach

Wight

et al. 2019

Viruses

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“…Metaphase spreads were generated as described previously (Kaufer et al, 2011). The virus genome was detected using a HHV-6A-specific digoxigenin-labeled probe and detected using different antibodies as described by Wight et al (2018). Slides were mounted using DAPI Vectashield (Vector Laboratories) and images taken with an Axio Imager M1 (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

Chromatin Profiles of Chromosomally Integrated Human Herpesvirus-6A

et al. 2019

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Human herpesvirus-6A (HHV-6A) and 6B (HHV-6B) are two closely related betaherpesviruses that are associated with various diseases including seizures and encephalitis. The HHV-6A/B genomes have been shown to be present in an integrated state in the telomeres of latently infected cells. In addition, integration of HHV-6A/B in germ cells has resulted in individuals harboring this inherited chromosomally integrated HHV-6A/B (iciHHV-6) in every cell of their body. Until now, the viral transcriptome and the epigenetic modifications that contribute to the silencing of the integrated virus genome remain elusive. In the current study, we used a patient-derived iciHHV-6A cell line to assess the global viral gene expression profile by RNA-seq, and the chromatin profiles by MNase-seq and ChIP-seq analyses. In addition, we investigated an in vitro generated cell line (293-HHV-6A) that expresses GFP upon the addition of agents commonly used to induce herpesvirus reactivation such as TPA. No viral gene expression including miRNAs was detected from the HHV-6A genomes, indicating that the integrated virus is transcriptionally silent. Intriguingly, upon stimulation of the 293-HHV-6A cell line with TPA, only foreign promoters in the virus genome were activated, while all HHV-6A promoters remained completely silenced. The transcriptional silencing of latent HHV-6A was further supported by MNase-seq results, which demonstrate that the latent viral genome resides in a highly condensed nucleosome-associated state. We further explored the enrichment profiles of histone modifications via ChIP-seq analysis. Our results indicated that the HHV-6 genome is modestly enriched with the repressive histone marks H3K9me3/H3K27me3 and does not possess the active histone modifications H3K27ac/H3K4me3. Overall, these results indicate that HHV-6 genomes reside in a condensed chromatin state, providing insight into the epigenetic mechanisms associated with the silencing of the integrated HHV-6A genome.

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“…Each DR contains two stretches of the human telomere hexameric repeat (TTAGGG) n , which are important for integration in vitro [12]. For this reason, homologous recombination has been proposed to be involved in integration, however the exact mechanism is not clear [13,14].…”

Section: Introductionmentioning

confidence: 99%

Endogenization and excision of human herpesvirus 6 in human genomes

et al. 2020

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Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one

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Viral Proteins U41 and U70 of Human Herpesvirus 6A Are Dispensable for Telomere Integration

Cited by 17 publications

References 35 publications

The Role of Marek’s Disease Virus UL12 and UL29 in DNA Recombination and the Virus Lifecycle

The Role of Marek’s Disease Virus UL12 and UL29 in DNA Recombination and the Virus Lifecycle

Chromatin Profiles of Chromosomally Integrated Human Herpesvirus-6A

Endogenization and excision of human herpesvirus 6 in human genomes

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