EBV particles induce chromosome instability

Infections with the Epstein-Barr virus (EBV) are associated with cancer development, and EBV lytic replication, the process that generates virus progeny is a strong risk factor for some cancer types. We have recently reported that EBV infection of B-lymphocytes in vitro and in a mouse model leads to an increased rate of centrosome amplification (Figure 1), associated with chromosomal instability (Figure 2). Importantly, this effect can be reproduced with virus-like particles devoid of EBV DNA, but not with defective virus-like particles that cannot infect host cells because they lack a glycoprotein involved in target cell entry.

 

We could identify the viral tegument protein BNRF1 as an inducer of centrosome amplification though over-duplication of the centrosome machinery. EBV mutants that lack BNRF1 have lost this property but it can be restored by reintroduction of the BNRF1 protein into the virus particle. Importantly, BNRF1 localizes to the centrosome compartment in transfected cells. This identifies a new mechanism by which EBV particles can induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for development of tumors that do not necessarily carry the viral genome.

 

Future projects will aim at understanding the mechanisms that lead to centrosome over-duplication. This includes the delineation of the domains of this protein that allow recruitment to the centrosome and those that mediate the overduplication, the identification of interacting proteins, and a definition of the protein structure using multiple techniques.

Figure 1: EBV-infected cells show centrosome overduplication. Cells infected with Epstein-Barr virus were cytospinned and stained with DAPI, an antibody specific to alpha-tubulin t visualize the mitotic spindle or an antibody specific to centrin-2. The centrin-2 staining highlights the centrioles. The upper panel shows an interphase cell with more than 2 centrioles. The lower panel shows a tripolar mitosis organized around an increased number of centrioles.
© dkfz.de

Figure 2: Chromosome abnormalities in EBV-infected cells. Cells infected with EBV were submitted to an M-FISH analysis. This mitosis shows a partial deletion of chromosome 11 and a trisomy of chromosomes 1, 2, 6, 7, 8.
© dkfz.de

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