The Latency-Associated Nuclear Antigen Tethers the Kaposi's Sarcoma-Associated Herpesvirus Genome to Host Chromosomes in Body Cavity-Based Lymphoma Cells

Abstract

Viruses that establish latent infection must maintain their DNA in the host nucleus through many cellular generations. Here we identify a novel mechanism by which the gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) may achieve this persistence in latently infected body cavity-based lymphoma (BCBL) cells. We find that KSHV genomic DNA is associated with host chromosomes and colocalizes with the latency-associated nuclear antigen (LANA). Furthermore, a region at the left end of the KSHV genome binds strongly to LANA and can colocalize to the host chromosomes with LANA. Additionally, we found that LANA associates with histone H1 in KSHV-infected BCBL cells. We propose that this chromosomal association of the KSHV genome is mediated by LANA and involves a tethering mechanism by which viral episomes are linked to host chromatin through simultaneous interaction with host chromosomal proteins including histone H1 and cis-acting KSHV DNA elements. This strategy may be employed by other viruses in establishment of latency in the infected cells.

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

“…Both N-terminal LANA (N-LANA) and C-terminal LANA (C-LANA) are essential for function. N-LANA associates with mitotic chromosomes via binding histones H2A/H2B, and C-LANA simultaneously binds KSHV terminal repeat (TR) DNA (7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Thus, LANA tethers the viral genome to host chromosomes and distributes viral DNA to daughter nuclei during mitosis.…”

Viral epigenomes in human tumorigenesis

“…LANA participates in the maintenance of the episome during latency. It also links the episome to the host cell chromosome and binds to the viral repeat elements (TR) of the viral genome to mediate its replication (Ballestas et al, 1999;Cotter and Robertson, 1999;Verma et al, 2007). The interactions between LANA and cellular and viral proteins, such as those encoded by p53, pRB or replication and transcription activator (Rta), among others, are summarized by zur Hausen (2006), who also reviews its regulatory role in the expression of genes involved in the main cellular pathways.…”

Development of a fluorescence-based assay to screen antiviral drugs against Kaposi's sarcoma–associated herpesvirus

“…LANA plays a pivotal role in the maintenance and segregation of the viral genome during latency (12), and thus, is also essential for cell survival (13). Maintenance of the viral genome is absolutely dependent on the LANA protein, which tethers the latent viral episome to the host cell chromosome, ensuring that the viral genome is replicated with the host genome and is not diluted out of the expanding population of latently infected cells (14,15). If the viral episome is lost, LANA and the other latent viral oncogenes are no longer expressed, and the tumor cell dies.…”