The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Li, Shijun; Tan, Min; Juillard, Franceline; Ponnusamy, Rajesh; Correia, Bruno E.; Simas, J. Pedro; Carrondo, Maria Arménia; McVey, Colin E.; Kaye, Kenneth M.

doi:10.1074/jbc.m115.674622

Cited by 4 publications

(5 citation statements)

References 67 publications

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“…A recent study by Li et al showed that dorsal positively charged electrostatic patch within the LANA DBD plays a crucial role in KSHV latent DNA replication and genome maintenance (Han et al, 2010 ). LANA DBD interacts with BET (Bromodomain and Extra Terminal domain) family of proteins (Ottinger et al, 2006 ; You et al, 2006 ), comprising of BRD2, BRD3, and BRD4, which are known to associate with acetylated histones (Li et al, 2015 ). BET family of proteins are transcriptional regulators, which play an important role in cell cycle control.…”

Section: Mechanism Of Kshv Latent Dna Replicationmentioning

confidence: 99%

KSHV Genome Replication and Maintenance

et al. 2016

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Kaposi's sarcoma associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is a major etiological agent for multiple severe malignancies in immune-compromised patients. KSHV establishes lifetime persistence in the infected individuals and displays two distinct life cycles, generally a prolonged passive latent, and a short productive or lytic cycle. During latent phase, the viral episome is tethered to the host chromosome and replicates once during every cell division. Latency-associated nuclear antigen (LANA) is a predominant multifunctional nuclear protein expressed during latency, which plays a central role in episome tethering, replication and perpetual segregation of the episomes during cell division. LANA binds cooperatively to LANA binding sites (LBS) within the terminal repeat (TR) region of the viral episome as well as to the cellular nucleosomal proteins to tether viral episome to the host chromosome. LANA has been shown to modulate multiple cellular signaling pathways and recruits various cellular proteins such as chromatin modifying enzymes, replication factors, transcription factors, and cellular mitotic framework to maintain a successful latent infection. Although, many other regions within the KSHV genome can initiate replication, KSHV TR is important for latent DNA replication and possible segregation of the replicated episomes. Binding of LANA to LBS favors the recruitment of various replication factors to initiate LANA dependent DNA replication. In this review, we discuss the molecular mechanisms relevant to KSHV genome replication, segregation, and maintenance of latency.

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Section: Mechanism Of Kshv Latent Dna Replicationmentioning

confidence: 99%

KSHV Genome Replication and Maintenance

et al. 2016

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“…As in E2 and EBNA, the C-terminal domain of LANA is the specific DNA binding/dimerization domain that forms a beta-barrel core with surface recognition alpha helices that contact residues in the LBS motif (42,56,57). On the face of the domain opposite from the recognition helix is a basic patch that interacts with cellular factors and impacts KSHV plasmid maintenance (58,59). The N-terminal CBD is primarily responsible for host chromosome binding, but sequences in the C-terminal DBD can also mediate binding to pericentromeric and telomeric regions of host chromosomes (60)(61)(62).…”

Section: Kaposi's Sarcoma-associated Herpesvirusmentioning

confidence: 99%

Hitchhiking of Viral Genomes on Cellular Chromosomes

Coursey

McBride

2019

Annu. Rev. Virol.

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Persistent viral infections require a host cell reservoir that maintains functional copies of the viral genome. To this end, several DNA viruses maintain their genomes as extrachromosomal DNA minichromosomes in actively dividing cells. These viruses typically encode a viral protein that binds specifically to viral DNA genomes and tethers them to host mitotic chromosomes, thus enabling the viral genomes to hitchhike or piggyback into daughter cells. Viruses that use this tethering mechanism include papillomaviruses and the gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. This review describes the advantages and consequences of persistent extrachromosomal viral genome replication.

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“…This positive patch serves to interact with BET proteins, although BET proteins also interact with a second region (residues 1125–1129) in C-terminal LANA ( Hellert et al, 2013 ). Mutation of the positive patch reduced LANA’s ability to mediate DNA replication and episome persistence, and mutation of the peripheral region of the positive patch generated the most severe effects, compared to mutation of other portions of the patch ( Correia et al, 2013 ; Domsic et al, 2013 ; Hellert et al, 2013 ; Li et al, 2015 ). These deficiencies in replication and maintenance were unrelated to BET protein binding ( Correia et al, 2013 ; Li et al, 2015 ).…”

Section: Lana Mediates Kshv Genome Persistencementioning

confidence: 99%

“…Mutation of the positive patch reduced LANA’s ability to mediate DNA replication and episome persistence, and mutation of the peripheral region of the positive patch generated the most severe effects, compared to mutation of other portions of the patch ( Correia et al, 2013 ; Domsic et al, 2013 ; Hellert et al, 2013 ; Li et al, 2015 ). These deficiencies in replication and maintenance were unrelated to BET protein binding ( Correia et al, 2013 ; Li et al, 2015 ). Mutation of the analogous positive patch in MHV68 LANA impacted the ability of MHV68 to establish latent infection in mice ( Correia et al, 2013 ; Hellert et al, 2013 ).…”

Section: Lana Mediates Kshv Genome Persistencementioning

confidence: 99%

Kaposi’s Sarcoma Herpesvirus Genome Persistence

Juillard

Tan

et al. 2016

Front. Microbiol.

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Kaposi’s sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. These diseases are most common in immunocompromised individuals, especially those with AIDS. Similar to all herpesviruses, KSHV infection is lifelong. KSHV infection in tumor cells is primarily latent, with only a small subset of cells undergoing lytic infection. During latency, the KSHV genome persists as a multiple copy, extrachromosomal episome in the nucleus. In order to persist in proliferating tumor cells, the viral genome replicates once per cell cycle and then segregates to daughter cell nuclei. KSHV only expresses several genes during latent infection. Prominent among these genes, is the latency-associated nuclear antigen (LANA). LANA is responsible for KSHV genome persistence and also exerts transcriptional regulatory effects. LANA mediates KSHV DNA replication and in addition, is responsible for segregation of replicated genomes to daughter nuclei. LANA serves as a molecular tether, bridging the viral genome to mitotic chromosomes to ensure that KSHV DNA reaches progeny nuclei. N-terminal LANA attaches to mitotic chromosomes by binding histones H2A/H2B at the surface of the nucleosome. C-terminal LANA binds specific KSHV DNA sequence and also has a role in chromosome attachment. In addition to the essential roles of N- and C-terminal LANA in genome persistence, internal LANA sequence is also critical for efficient episome maintenance. LANA’s role as an essential mediator of virus persistence makes it an attractive target for inhibition in order to prevent or treat KSHV infection and disease.

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The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence

Cited by 4 publications

References 67 publications

KSHV Genome Replication and Maintenance

KSHV Genome Replication and Maintenance

Hitchhiking of Viral Genomes on Cellular Chromosomes

Kaposi’s Sarcoma Herpesvirus Genome Persistence

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