Wistar Institute Scientists Discover Pathway That Could Be Targeted In Fighting Epstein-Barr Virus

Researchers at The Wistar Institute have discovered a pathway that therapeutics could potentially target to contain Epstein-Barr virus (EBV).

The Wistar Institute

The Wistar Institute. Image Courtesy of WI

The team found that the virus made use of two cellular proteins, CTCF, and PARP1, to regulate its gene expression. These same proteins also regulate the expression of the human genome. They, therefore, provide a crafty way for the virus to duplicate its genome.

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PARP1 is known more as a protein that plays a part in DNA damage and repair. This study shows that it has another role as relates to the regulation of the EBV genome.

An implication of this research is that existing drugs targeting PARP1 could disrupt EBV genome folding that results in diseases.

The Wistar Institute is a global leader in biomedical research on cancer, infectious disease, immunology, and vaccine development.

A common infection

EBV infection is a highly prevalent one. Estimates have it that it affects over 90 percent of the world’s population. This commonness is not so much of a concern because the infection is usually not harmful.

EBV, however, has the potential to increase the risk of multiple diseases. As a dynamic virus, it is capable of altering its gene expression. The virus can infect B-cells if there is an expression of certain viral genes, causing them to reproduce too much.

A change in gene expression of EBV can constitute a greater risk to people with weakened immune systems. The virus increases the risk of developing certain cancer types that are linked to B-cells, especially nasopharyngeal carcinoma.

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EBV is also well-known to play a part in the incidence of multiple sclerosis. It remains a mystery, however, why a lot more people do not have the disorder given the large proportion of the population that is infected.

Probing the manipulation of EBV’s genetic expression

Researchers set out in this study to figure out how EBV manages to manipulate the cells of its host to duplicate its own genome.

The virus does not merge its genome into that of host cells but maintains it separately as an episome, a circular chromosome. With the aid of its diverse latency states, the episome can replicate its genome during the division of host cells.

“The virus was clever to use the same machinery that regulates the conformation of the human genome to also regulate its own gene expression,” the study’s corresponding author Italo Tempera noted.

The DNA inside a chromosome has to be coiled or folded many times to fit into the nucleus of a cell. This is necessary because the genetic information storage can otherwise extend several meters in length.

Researchers investigated in this study how the EBV genome folds under various conditions. They did this through a modified DNA sequencing procedure.

Tempera and his colleagues were surprised to find that the EBV genome can fold in a certain way that has implications for function. The folding looked very different at various stages of infection.

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The team identified PARP1 and CTCF, a chromatin-binding protein, as playing a part in how the virus manipulates folding and gene expression.

The drug olaparib (Lynparza), which is approved for the treatment of people with ovarian cancer, targets PARP1. Scientists found that such a PARP inhibitor can also reprogram EBV and how its genes are expressed.

New research also shows that olaparib may be useful for the treatment of cancers linked to EBV.

“Our paper shows that there is another role of PARP1 in the chromatin folding,” Tempera said, “so this suggests that maybe we can expand the way in which we can use this drug not only to interfere with DNA damage, but we also might interfere with DNA folding and gene expression, which is something that we are testing now in the lab.”

The researchers are also looking to explore what role, if any, PARP1 plays in the human genome’s folding.

References

The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity

Targeting PARP could fight cancer-associated virus

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