The ubiquitous Epstein-Barr virus targets “fragile DNA,” triggering dysfunction that is related with a wide variety of cancers.
Researchers have found how the Epstein-Barr virus (EBV) exploits human genomic weaknesses to trigger cancer and suppress the body’s defenses. The study shows that the EBNA1 viral protein binds to a fragile internet site on human chromosome 11, major to chromosomal breakage and genomic instability that may perhaps outcome in cancer. This locating could assist recognize threat aspects and create preventative tactics for EBV-related ailments.
The Epstein-Barr virus (EBV) is simply spread by means of bodily fluids, mostly saliva, such as kissing, shared drinks, or working with the exact same consuming utensils. Not surprisingly then, EBV is also amongst the most ubiquitous of viruses: Much more than 90% of the world’s population has been infected, normally through childhood.
EBV causes infectious mononucleosis and equivalent ailments, even though usually there are no symptoms. Most infections are mild and pass, but the virus persists in the physique, becoming latent or inactive, at times reactivating. Lengthy-term latent infections are related with many chronic inflammatory situations and a number of cancers.
In a new paper, published April 12, 2023, in the journal Nature, researchers at University of California San Diego, UC San Diego Moores Cancer Center, and Ludwig Cancer Investigation at UC San Diego, describe for the 1st time how the virus exploits genomic weaknesses to trigger cancer though minimizing the body’s potential to suppress it.
These findings show “how a virus can induce cleavage of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate a key tumor suppressor,” stated senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at UC San Diego College of Medicine.
“It’s the 1st demonstration of how cleavage of a ‘fragile DNA’ internet site can be selectively induced.”
All through just about every person’s genome or complete set of genes are fragile web pages, precise chromosomal regions additional probably to generate mutations, breaks or gaps when replicating. Some are uncommon, some are frequent all are related with issues and illness, at times heritable situations, at times not, such as a lot of cancers.
In the new study, Cleveland and colleagues concentrate on EBNA1, a viral protein that persists in cells infected with EBV. EBNA1 was previously recognized to bind at a precise genomic sequence in the EBV genome at the origin of replication. The researchers located that EBNA1 also binds a cluster of EBV-like sequences at a fragile internet site on human chromosome 11 exactly where growing abundance of the protein triggers chromosomal breakage.
Other prior analysis has shown that EBNA1 inhibits p53, a gene that plays a crucial part in controlling cell division and cell death. It also suppresses tumor formation when standard. Mutations of p53, on the other hand, are linked to cancer cell development.
When the scientists examined entire-genome sequencing information for two,439 cancers across 38 tumor sorts from the Pan-Cancer Evaluation of Entire Genomes project, they located that cancer tumors with detectable EBV revealed larger levels of chromosome 11 abnormalities, which includes one hundred% of the head and neck cancer situations.
“For a ubiquitous virus that is harmless for the majority of the human population, identifying at-threat men and women susceptible to the improvement of latent infection-related ailments is nonetheless an ongoing work,” stated the study’s 1st author Julia Li, PhD, a postdoctoral fellow in Cleveland’s lab.
“This discovery suggests that susceptibility to EBNA1-induced fragmentation of chromosome 11 depends on the manage of EBNA1 levels developed in latent infection, as effectively as the genetic variability in the quantity of EBV-like sequences present on chromosome 11 in every person. Going forward, this understanding paves the way for screening threat aspects for the improvement of EBV-related ailments. Furthermore, blocking EBNA1 from binding at this cluster of sequences on chromosome 11 can be exploited to protect against the improvement of EBV-related ailments.”
Reference: “Chromosomal fragile internet site breakage by EBV-encoded EBNA1 at clustered repeats” by Julia Su Zhou Li, Ammal Abbasi, Dong Hyun Kim, Scott M. Lippman, Ludmil B. Alexandrov and Don W. Cleveland, 12 April 2023, Nature.
Co-authors incorporate: Julia Su Zhou Li, Ludwig Cancer Investigation and UC San Diego Ammal Abbasi, Scott M. Lippman and Ludmil B. Alexandrov, UC San Diego and Dong Hyun Kim, Ludwig Cancer Investigation, UC San Diego.