Kaposi’s Sarcoma-Associated Herpesvirus LANA Hitches a Ride on the Chromosome

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) latently infects tumor cells and has an etiologic role in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Survival in rapidly dividing cells depends on a carefully orchestrated chain of events. The viral genome, or episome, must replicate in concert with cellular genetic material, and then efficiently segregate to progeny nuclei. KSHV achieves this through its latency associated nuclear antigen (LANA), which simultaneously binds to viral DNA and mitotic chromosomes to efficiently partition episomes. LANA’s N-terminal region has been shown to be essential for efficient KSHV DNA replication and tethering to mitotic chromosomes. The precise mechanism by which LANA attaches to host chromosomes has been an area of active investigation. We recently reported that this association is mediated by the chromatin components histones H2A and H2B. Binding between LANA and these proteins was demonstrated in vivo and in vitro, and use of an H2A-H2B depleted system demonstrated their central role in LANA’s chromosome binding. Further, we provided a structural description of the interaction of LANA’s N-terminal chromosome association region with the nucleosome using x-ray crystallography. Our data offer further insight into the mechanism of KSHV latency, and also reveal a new concept for a role of the nucleosome as a docking site for other proteins.