Efficient Persistence of Extrachromosomal KSHV DNA Mediated by Latency-Associated Nuclear Antigen

Abstract

Primary effusion lymphoma (PEL) cells harbor Kaposi's sarcoma-associated herpesvirus (KSHV) episomes and express a KSHV-encoded latency-associated nuclear antigen (LANA). In PEL cells, LANA and KSHV DNA colocalized in dots in interphase nuclei and along mitotic chromosomes. In the absence of KSHV DNA, LANA was diffusely distributed in the nucleus or on mitotic chromosomes. In lymphoblasts, LANA was necessary and sufficient for the persistence of episomes containing a specific KSHV DNA fragment. Furthermore, LANA colocalized with the artificial KSHV DNA episomes in nuclei and along mitotic chromosomes. These results support a model in which LANA tethers KSHV DNA to chromosomes during mitosis to enable the efficient segregation of KSHV episomes to progeny cells.

Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

“…LANA is a 222-232-kDa nuclear protein expressed from open reading frame 73 of the KSHV genome [4,7,8,9]. LANA contains several conserved sequences including acidic-, proline-, and glutamine-rich domains as well as a zinc finger DNA-binding domain, leucine zipper, and potential nuclear localization signal.…”

“…Its domain structure suggests that LANA plays a pivotal role in KSHV-infected cells. Indeed, LANA tethers the viral genome to the host cell genome, thus it is involved in long-term maintenance of viral episomal DNA in dividing cells [7,8,9]. In addition, LANA interacts with a variety of cellular proteins in the host.…”

“…Although KSHV was originally isolated from Kaposi's sarcoma (KS), the virus is also related to primary effusion lymphoma and multicentric Castleman disease [5,6]. Latency-associated nuclear antigen (LANA), a KSHV protein, is critical for the persistence of KSHV episomes, and functions in this capacity by tethering viral episomes to chromosomes during mitosis [7,8,9]. In addition, LANA interacts physically with various cellular proteins that regulate transcriptional activities, resulting in interfering with critical regulators of the cell cycle and enhancing anti-apoptotic effects [10,11,12,13].…”

The Viral Etiology of AIDS‐Associated Malignancies

“…The KSHV LANA is a nuclear phosphoprotein that is important for the maintenance of viral latency (Dittmer et al, 1998). It has been shown to bind to the terminal repeat region of the viral genome and tethered the viral episome to the host chromosome so that it can be maintained during cellular mitotic replication and segregation (Ballestas et al, 1999;Cotter et al, 2001). LANA is a multifunctional viral protein and can bind to a number of cellular proteins.…”

Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

“…LANA is one of the few latent genes expressed in KSHV-infected PEL cell lines. It tethers viral DNA to host chromosomes to ensure efficient viral replication (Ballestas et al, 1999). In addition, LANA associates with various proteins including p53 and pRb and through these interactions stimulates pathways involved in survival and proliferation (Friborg et al, 1999;Radkov et al, 2000).…”