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Abstract
The capacity of gamma-herpesviruses to establish lifelong infections is dependent on the expression of genome maintenance proteins (GMPs) that tether the viral episomes to cellular chromatin and allow their persistence in latently infected proliferating cells. Here we have characterized the chromatin interaction of GMPs encoded by viruses belonging to the genera Lymphocryptovirus (LCV) and Rhadinovirus (RHV). We found that, in addition to a similar diffuse nuclear localization and comparable detergent resistant interaction with chromatin in transfected cells, all GMPs shared the capacity to promote the decondensation of heterochromatin in the A03-1 reporter cell line. They differed, however, in their mobility measured by fluorescence recovery after photobleaching (FRAP), and in the capacity to recruit accessory molecules required for the chromatin remodeling function. While the AT-hook containing GMPs of LCVs were highly mobile, a great variability was observed among GMPs encoded by RHV, ranging from virtually immobile to significantly reduced mobility compared to LCV GMPs. Only the RHV GMPs recruited the bromo- and extra terminal domain (BET) proteins BRD2 and BRD4 to the site of chromatin remodeling. These findings suggest that differences in the mode of interaction with cellular chromatin may underlie different strategies adopted by these viruses for reprogramming of the host cells during latency.
Highlights
A distinctive characteristic of herpesviruses is the capacity to establish lifelong infections where the virus persists in healthy carriers by hiding in a cellular reservoir that expresses only few latency-associated viral genes
All gamma-herpesviruses express proteins, known as the Genome Maintenance Proteins (GMPs), that share two common characteristics: (i) they can initiate the replication of viral episomes in latently infected cells and coordinate the replication of the viral and cellular genomes during S-phase, and (ii) they act as bridges to tether the viral episomes to the host cell chromosomes during mitosis, ensuring thereby their correct partitioning between daughter cells [1]
We report that all tested GMPs were capable of inducing the decondensation of heterochromatin in A03-1 cells, but they differed in mobility measured by Fluorescence Recovery after Photobleaching (FRAP) and in the capacity to recruit accessory molecules required for the chromatin remodeling function
Summary
A distinctive characteristic of herpesviruses is the capacity to establish lifelong infections where the virus persists in healthy carriers by hiding in a cellular reservoir that expresses only few latency-associated viral genes. Members of the lymphotropic gamma-herpesvirus subfamily establish latency in proliferating cells and have evolved specific strategies to avoid loss of the viral episomes during cell division To this end, all gamma-herpesviruses express proteins, known as the Genome Maintenance Proteins (GMPs), that share two common characteristics: (i) they can initiate the replication of viral episomes in latently infected cells and coordinate the replication of the viral and cellular genomes during S-phase, and (ii) they act as bridges to tether the viral episomes to the host cell chromosomes during mitosis, ensuring thereby their correct partitioning between daughter cells [1]. Recruitment of LANA1 to mouse chromosomes was shown to require methyl CpG-binding protein (MeCP2) and DEK [14], which may facilitate nucleosome binding, while the Cterminal domain interacts with several chromatin-binding proteins including BRD4, BRD2/Ring, Histone H1 and the nuclear mitotic apparatus protein NuMA [15,16]
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