A new breakthrough study has uncovered a link between Epstein-Barr virus (EBV) and genomic instability. EBV is a herpesvirus that can cause several cancers of lymphocytic and epithelial origin. EBV encodes a protein called EBNA1, which helps in viral persistence. EBNA1 binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome and also associates with host chromosomes at non-sequence-specific sites.
Researchers have found that the sequence-specific DNA-binding domain of EBNA1 binds to a cluster of tandemly repeated copies of an EBV-like, 18-base-pair imperfect palindromic sequence on human chromosome 11q23. The region spans about 21 kilobases and is associated with inherently fragile DNA, as evidenced by aberrant structures on mitotic chromosomes. Increasing levels of EBNA1 binding triggers dose-dependent breakage at 11q23, resulting in a fusogenic centromere-containing fragment and an acentric distal fragment that mis-segregate into micronuclei in the next cell cycle.
In a recent study published in Nature, the researchers discovered how EBV exploits human genomic weaknesses to cause cancer and suppress the body’s defences. The binding of EBNA1 viral protein to a fragile site located on human chromosome 11 causes chromosomal breakage and genomic instability that could potentially lead to cancer. This discovery could help identify risk factors and develop preventative strategies for EBV-associated diseases.
The study revealed that EBNA1, a viral protein that persists in cells infected with EBV, binds to a cluster of EBV-like sequences at a fragile site on human chromosome 11, where the increasing abundance of the protein triggers chromosomal breakage. Even a twofold increase in EBNA1 abundance can trigger breakage at 11q23 in cells latently infected with EBV.
Whole-genome sequencing of EBV-associated nasopharyngeal carcinomas showed that structural variants are highly enriched on chromosome 11. At the same time, the presence of EBV was associated with an enrichment of chromosome 11 rearrangements across 2,439 tumors from 38 cancer types.
Moreover, the researchers found that cancer tumors with detectable EBV revealed higher levels of chromosome 11 abnormalities, including 100% of the head and neck cancer cases. This suggests that an individual’s susceptibility to EBNA1-induced fragmentation of chromosome 11 is influenced by two factors: the control of EBNA1 levels produced during latent infection and the genetic variability in the number of EBV-like sequences present on chromosome 11.
These findings highlight a previously unknown link between EBV and genomic instability, demonstrating how EBNA1-induced breakage at 11q23 triggers the acquisition of structural variations in chromosome 11, ultimately leading to the development of cancer. This study provides critical insights into the mechanisms by which the Epstein-Barr virus causes cancer and suppresses the body’s defenses. Identifying at-risk individuals susceptible to the development of latent infection-associated diseases is an ongoing effort, and this discovery has the potential to help identify those individuals and develop preventative strategies.