The Epstein-Barr virus (EBV) is easily transmitted through bodily fluids, mainly saliva, such as kissing, sharing drinks, or using the same eating utensils. It is not surprising, then, that EBV is also among the most ubiquitous viruses: more than 90% of the world’s population has been infected, usually during childhood.
EBV causes infectious mononucleosis and similar conditions, although it often has no symptoms. Most infections are mild and pass, but the virus persists in the body, lying dormant or inactive, and sometimes reactivating. Long-term latent infections are associated with various chronic inflammatory conditions and multiple types of cancer.
In a new article, published on April 12, 2023 in the journal NatureResearchers from the University of California San Diego, UC San Diego Moores Cancer Center, and Ludwig Cancer Research at UC San Diego describe for the first time how the virus exploits genomic weaknesses to cause cancer while reducing the body’s ability to to delete it.
These findings show “how a virus can induce excision of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate an important tumor suppressor,” said study lead author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences, and Cellular and Molecular Medicine at the UC San Diego School of Medicine.
“This is the first demonstration of how cleavage of a ‘fragile DNA’ site can be selectively induced.”
Throughout each person’s genome or entire set of genes there are fragile sites, specific chromosomal regions most likely to produce mutations, breaks, or gaps when replicating. Some are rare, some are common; they are all associated with disorders and diseases, sometimes hereditary conditions, sometimes not, like many types of cancer.
In the new study, Cleveland and his colleagues focus on EBNA1, a viral protein that persists in EBV-infected cells. It was previously known that EBNA1 binds to a specific genomic sequence in the EBV genome at the origin of replication. The researchers found that EBNA1 also binds to a cluster of EBV-like sequences at a fragile site on human chromosome 11 where increased abundance of the protein triggers chromosome breakage.
Other previous research has shown that EBNA1 inhibits p53, a gene that plays a key role in the control of cell division and cell death. It also suppresses tumor formation when normal. p53 mutations, on the other hand, are linked to the growth of cancer cells.
When scientists examined whole-genome sequencing data for 2,439 cancers across 38 tumor types from the Pan-Cancer Analysis of Whole Genomes project, they found that cancerous tumors with detectable EBV revealed higher levels of abnormalities on chromosome 11, including chromosome 11. 100% of head and neck cancer cases.
“For a ubiquitous virus that is harmless to the majority of the human population, identification of at-risk individuals susceptible to the development of diseases associated with latent infections remains an ongoing effort,” said study first author Julia Li, PhD, postdoctoral student. partner in the Cleveland lab.
“This finding suggests that susceptibility to EBNA1-induced chromosome 11 fragmentation depends on control of the levels of EBNA1 produced in latent infection, as well as genetic variability in the amount of EBV-like sequences present on chromosome 11 in each individual.”, this knowledge paves the way for the detection of risk factors for the development of diseases associated with EBV. Furthermore, blocking EBNA1 from binding to this set of sequences on chromosome 11 can be exploited to prevent the development of EBV-associated diseases.”