Epstein-Barr Virus (EBV) drives cancer by inducing DNA breakage and genome instability
Research PaperJulia Su Zhou Li et al., Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats. Nature. 616, 504-509 (2023).
Background and Scientific Question
Epstein-Barr Virus (EBV) or human herpesvirus 4 is a common infection in humans. EBV is contagious through body fluids like saliva and sexual contact. It has been associated with mononucleosis and cancer. Because EBV can cause cancer, it is an oncogenic herpesvirus.
Previous research indicated that persistence of the virus in cells increased risk of cancer. EBV persistence in cells was due to a protein called EBNA1 (EBV nuclear antigen 1). EBNA1 acts as a bridge between viral and human genomes. EBNA1 was thought to randomly bind to DNA sequences on the human genome. On the viral genome, EBNA1 can bind to specific sequences. Thus, EBNA1 acts as a bridge between the virus and genome in human cells.
However, the key question of how exactly EBNA1 binding to our genome is linked to cancer remained unanswered.
Experiments and Results
In this research paper, the authors addressed the above question. They used recombinant DNA technology to generate a version of EBNA1 that can be observed by microscopy in the laboratory. They injected this protein in to cultured human cells and observed EBNA1 under the microscope.
They observed that EBNA1 bound to specific sequences on the chromosomes of these cultured cells. They were also able to identify the region (domain) on the protein that bound to chromosomes. This is called the DNA Binding Domain (DBD). They were also able to identify the sequence on the chromosome of cells to which EBNA1 was bound. It was a cluster of an 18 base pair sequence located on longer arm (q arm) of chromosome 11. This region can be identified as 11q23.
They eventually went on to discover that this binding of EBNA1 to the chromosome 11q23 triggers its breakage. Chromosome breakage causes genome instability which is an enabling characteristic of cancer. In addition, chromosome breakage also causes structural variations along chromosome 11, another driver of cancer.
Conclusions and Outlook
The authors of this research paper have identified the mechanism by which Epstein-Barr Virus (EBV) triggers cancer development. A protein encoded by EBV, called EBNA1 binds to DNA of our cells on chromosome 11q23. This binding triggers DNA breakage and structural variations of chromosome 11. This leads to genome instability which enables cancer.
The authors conclude their research paper by writing,
Since the initial discovery of 51 fragile sites in human chromosomes almost 40 years ago, we have now identified an example of fragility induced by binding of EBNA1, the sequence-specific DNA-binding protein encoded by a virus to which almost the entire human population has been exposed.