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. 2012 Jan 24:3:7.
doi: 10.3389/fmicb.2012.00007. eCollection 2012.

Kaposi's Sarcoma-Associated Herpesvirus Genome Replication, Partitioning, and Maintenance in Latency

Eriko Ohsaki  1 , Keiji Ueda
Affiliations

Kaposi's Sarcoma-Associated Herpesvirus Genome Replication, Partitioning, and Maintenance in Latency

Eriko Ohsaki et al. Front Microbiol. .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is thought to be an oncogenic member of the γ-herpesvirus subfamily. The virus usually establishes latency upon infection as a default infection pattern. The viral genome replicates according to the host cell cycle by recruiting the host cellular replication machinery. Among the latently expressing viral factors, LANA plays pivotal roles in viral genome replication, partitioning, and maintenance. LANA binds with two LANA-binding sites (LBS1/2) within a terminal repeat (TR) sequence and is indispensable for viral genome replication in latency. The nuclear matrix region seems to be important as a replication site, since LANA as well as cellular replication factors accumulate there and recruit the viral replication origin in latency (ori-P) by its binding activity to LBS. KSHV ori-P consists of LBS followed by a 32-bp GC-rich segment (32GC). Although it has been reported that LANA recruits cellular pre-replication complexes (pre-RC) such as origin recognition complexes (ORCs) to the ori-P through its interaction with ORCs, this mechanism does not account completely for the requirement of the 32GC. On the other hand, there are few reports about the partitioning and maintenance of the viral genome. LANA interacts with many kinds of chromosomal proteins, including Brd2/RING3, core histones, such as H2A/H2B and histone H1, and so on. The detailed molecular mechanisms by which LANA enables KSHV genome partitioning and maintenance still remain obscure. By integrating the findings reported thus far on KSHV genome replication, partitioning, and maintenance in latency, we will summarize what we know now, discuss what questions remain to be answered, and determine what needs to be done next to understand the mechanisms underlying viral replication, partitioning, and maintenance strategy.

Keywords: DNA replication; Kaposi’s sarcoma-associated herpesvirus; genome maintenance; human herpesvirus 8; latency-associated nuclear antigen; nuclear matrix; ori-P; pre-replication complex.

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Figures

Figure 1
Figure 1
Terminal repeat (TR) sequences. The KSHV genome has 40–50 units of TR sequences. TR contains LANA-binding site (LBS) and GC-rich sequences termed 32GC. It is thought that one of the LBS-32GC sequence is selected as DNA replication origin (ori-P).
Figure 2
Figure 2
Organization of LANA and its interacting proteins. The top Figure shows the organization of the LANA protein. LANA has two nuclear localization signals (NLS): one at the N-terminal region and the other at the C-terminal region. The former is a primary NLS and the latter is cryptic. A chromosome binding site (CBS) was reported to be present at the N-terminal end as a histone H1 binding region. The mid-part of LANA consists of a very peculiar amino acid composition called a proline-rich region (P-rich), an extremely aspartate (D)- and glutamate (E)-rich region (DE) and a glutamine (Q)-aspartate (D)-glutamate (E)-rich region (QQQDE/QQQQDE). LEE(D)QEQ(V)E looks like a leucine zipper but has not been recognized as a functional determinant. The C-terminal region has roles in both homo-dimerization and DNA binding to LBS. The main interacting proteins with LANA are listed below. The C-terminal region seems to be a region that interacts with many proteins.
Figure 3
Figure 3
A model for latent DNA replication of KSHV. LANA can associate with the nuclear matrix and can directly bind to the ori-P so that LANA can recruit the ori-P to the nuclear matrix. Cellular DNA replication machinery assembles to the nuclear matrix in a cell cycle-dependent manner, and is therefore available for viral DNA replication.
Figure 4
Figure 4
A model for KSHV genome segregation. The KSHV genome associates with the nuclear matrix through LANA, which exhibits nuclear matrix localization activity. DNA replication factories are supposed to anchor to the nuclear matrix, and DNA replication of the KSHV genome occurs on the nuclear matrix at the G1/S phase. Nuclear architectures, including the nuclear matrix, are disrupted at the prophase (nuclear envelope breakdown), and nuclear matrix proteins drastically change these functions and distributions; such as spindle pole or kinetochore proteins. It has been reported that KSHV LANA interacts with various proteins such as MeCP2, Brd2, Brd4, Histone H2A/B, Cenp-F, NuMA, Bub1, and so on. These interactions can associate a sister-chromatid with LANA, and thus KSHV genomes can separate into two daughter cells.
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