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Scientists are making a pivotal discovery about the underlying infection mechanism of the Epstein-Barr virus

The previously unknown enzymatic function of the viral EBNA1 protein may guide novel approaches to EBV-associated cancer

PHILADELPHIA – (January 21, 2021) – Researchers at the Westar Institute have discovered a new enzyme function for the Epstein-Barr virus protein (EBV), a critical factor in EBV’s ability to transform human cells and induce cancer. Posted in prison cell, This study introduces new indicators of EBNA1 function inhibition, and opens up new avenues for developing therapies to treat cancers associated with EBV.

EBV leads to a lifelong latent infection in B lymphocytes, which can contribute to the development of various types of cancer, including Burkitt’s lymphoma, nasopharyngeal cancer (NPC) and Hodgkin’s lymphoma.

Epstein-Barr nuclear antigen 1 (EBNA1) serves as an attractive therapeutic target for these cancers because it is expressed in all tumors associated with EBV, performs basic tumorigenic activities and no similar proteins are found in the human body.

“We detected an enzymatic activity of EBNA1 that had never been described before, despite extensive research efforts to characterize this protein,” said Paul M Lieberman, PhD, Hillary Koprovsky, MD, gifted professor, leader of the gene expression & regulation program at Westar, and author Corresponding to the study. “We found that EBNA1 has the hidden ability to cross-link and segment a single strand of DNA at the final stage of DNA replication. This may have important implications for other viral and cellular DNA-binding proteins that have enzyme-like activities encoding.”

Lieberman and colleagues also found that a specific EBNA1 amino acid called Y518 is necessary for this process to occur, and therefore for the viral DNA to persist in infected cells.

They generated a mutated EBNA1 protein in which an important amino acid was replaced by another and showed that this mutant could not form covalent bonding with DNA and perform nuclease activity responsible for generating single strand wounds.

In latent-infected cells, the EBV genome is conserved as a circular DNA molecule, or episome, that is transcribed by cellular enzymes along with the cell’s chromosomes. When a cell divides, the two adhesive genomes separate into two daughter cells.

While EBNA1 was known to mediate episome replication and division during host cell division, the exact mechanism was not clear. The new study highlights the process and describes how the newly discovered enzymatic activity of EBNA1 is required to complete viral genome replication and preserve the genetic profile.

Jayaraju Dheekollu, Ph.D., first author of the study, said: “Our findings indicate that one could create small molecules to ‘lock in’ the protein associated with DNA and potentially prevent termination of replication and maintenance episome, similar to the well-known topoisomerase inhibitors. In Lieberman’s lab. “These inhibitors can be used to prevent EBV-induced transformation and treat EBV-associated tumors.”

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Co-authors: Andreas Widmer, Kasiragan Ayanathan, Juliana S. Deakin, and Troy E. Messick from the Westar Institute. KA currently works at the University of Pennsylvania and JSD is currently working at GlaxoSmithKline.

Supported work: National Institutes of Health (NIH) awards RO1 CA093606, 1 423 DE017336, P30 CA010815, and T32 CA09171. The Westar Institute primary support was provided through the Cancer Center Support Grant P30CA010815.

Publication information: EBNA1-dependent cell cycle DNA crosslinking promotes termination of replication in oriP maintenance and viral Episome, prison cell (2021). Internet publishing.

The Wistar Institute is a leading global biomedical research institute with special expertise in cancer, immunology, infectious disease research and vaccine development. Founded in 1892 as the first non-profit independent biomedical research institute in the United States, Westar has been awarded the prestigious cancer center title from the National Cancer Institute since 1972. The institute has been actively working to ensure that research progress moves from the laboratory to the clinic as quickly as possible. wistar.org.

https: //Wistar.Deer /News /Press Releases /Wistar-scientists-made-axial-discovery-mechanism-Epstein-Bar-Kamen

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