Researchers map previously unseen herpes-telomere interaction.


A team of scientists, led by researchers at The Wistar Institute, has found that an infection with herpes simplex virus 1 (HSV-1) causes rearrangements in telomeres, small stretches of DNA that serve as protective ends to chromosomes. The findings show that this manipulation of telomeres may explain how viruses like herpes are able to successfully replicate while also revealing more about the protective role that telomeres play against other viruses.  The opensource study is published in Cell Reports.

Researchers know that telomeres play a very important part in the lifespan of a cell.  The team wanted to investigate whether they also play a role in either viral replication or protection from viruses, and the findings suggest, at least in the case of the herpes simplex virus, that this may indeed be the case.

Telomeres are often compared to the clear tips of shoelaces because they protect the end of chromosomes, the keepers of vital genetic information, and prevent them from fraying and breaking, thus preserving their ability to pass on necessary genetic information. Previously, the lab at Wistar has shown that viral DNA replication and maintenance share some common features with telomeres.  The team theorised that telomeres may serve as a barrier to viral replication and they wanted to explore whether that protection was at a physical level or a more molecular level.

Among the viruses the lab have decided to study is HSV-1, a particularly aggressive virus that replicates in the nucleus of a healthy cell where chromosomes and their telomeres reside. HSV-1 is a common virus that causes cold sores but can also cause more serious diseases including blindness and encephalitis. In the United States, approximately 65 percent of the population has antibodies to this particular strain of the virus as well as latent infections that can periodically reactivate to cause clinical symptoms. There is no vaccine for preventing HSV-1 infection and reactivation, and only a few effective treatments for the virus are available.

As detailed in the study, the lab found that HSV-1 is able to induce the transcription of telomere repeat-containing RNA (TERRA). This is followed by the virus degrading a telomere protein called TPP1, part of a complex of proteins responsible for protection called ‘telomere sheltering’ which results in the loss of the telomere repeat DNA signal.

When TPP1 becomes inhibited, the virus is able to increase its ability to replicate, suggesting that TPP1 normally provides some sort of protective function against this virus. HSV-1 is able to replicate more efficiently by disabling this protection. Finally, the virus uses a replication protein called ICP8 that works with the manipulated telomeric proteins to promote viral genomic replication.

The team summise that the current study expands knowledge of telomeres further in two very important ways.  First, it gives the medical community an indication that some viruses are able to manipulate telomeres specifically in order to replicate. Second, it appears that proteins like TPP1 provide very specific protective functions. These findings provide better understanding on just how telomeres may protect cells from viral infection.

Source:  The Wistar Institute

 

Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication.  HSV-1 Remodels Host Telomeres to Facilitate Viral Replication.  Lieberman et al 2014.

Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication. HSV-1 Remodels Host Telomeres to Facilitate Viral Replication. Lieberman et al 2014.

 

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