to the nucleus where it performs its replication-related functions. Origin-binding domain The OBD binds the viral genome's origin of replication by recognizing specific sequences that occur in the portion of the viral genome known as the non-coding control region. It also forms interactions with host cell proteins, such as replication protein A and Nbs1. The OBD is required for viral replication. Zinc-binding domain The zinc-binding and ATPase domains together comprise the helicase portion of the LTag protein. The primary function of the zinc-binding domain is oligomerization of LTag. Formation of dodecamer structures (two hexameric rings) is required for helicase activity, which begins at the origin of replication through coordination between the OBD, zinc-binding, and ATPase domains. ATPase domain The ATPase domain is a member of the AAA+ ATPase family and contains conserved motifs such as the ATP-binding Walker A box. Energy from ATP hydrolysis is required for helicase activity. The ATPase domain also contains regions responsible for protein-protein interactions with host cell proteins, most notably topoisomerase 1 and the cell cycle regulator p53. LTag is unique among known AAA+ ATPases in that it is capable of initiating the melting of DNA around the origin; in most such cases a distinct initiator protein is responsible for this step, after which the helicase continues unwinding. Function The major functions of LTag in the viral life cycle involve dysregulation of the host cell's cell cycle and replication of the virus's circular DNA genome. Because polyomavirus genome replication relies on the DNA replication machinery of the host cell, the cell must be in S phase (the part of the cell cycle in which the host cell's genome is normally replicated) in order to provide the necessary molecular machinery for viral DNA replication. The SV40 LTag can induce S phase and activate the host cell's DNA damage response. Coordinated actions of the OBD and helicase regions result in physical manipulation of the viral genome, melting the DNA double helix at the origin of replication and unwinding the circular DNA chromosome in a bidirectional fashion. The structure and function of LTag resembles that of the human papillomavirus oncoproteins. Expression LTag is encoded in the "early region" of the polyomavirus genome, so named because this region of the genome is expressed early in the infectious process. (The "late region" contains genes encoding the viral capsid proteins.) The early region typically contains at least two genes and is