Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Sun, Qiming; Tsurimoto, Toshiki; Juillard, Franceline; Li, Lin; Li, Shijun; Vázquez, Erika De León; Chen, She; Kaye, Kenneth M.

doi:10.1073/pnas.1404219111

Cited by 44 publications

(57 citation statements)

References 50 publications

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“…Both of these complexes have been shown to directly interact with LANA and to facilitate latent viral replication (33)(34)(35). Hypothesizing that LANA spirals may be induced in trans, the initiation sites for latent KSHV replication would not necessarily have to be restricted to the TR region.…”

Section: The Lana Dbd Exhibits Two Dna-binding Modesmentioning

confidence: 99%

The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

Hellert

Weidner-Glunde

Krausze

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

149

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Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNAbinding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains ("LANA speckles"), a hallmark of KSHV latency.X-ray crystallography | gammaherpesvirinae | viral latency | DNA-binding protein | KSHV LANA K aposi sarcoma herpesvirus (KSHV) is the only known γ 2 -herpesvirus of concern to human health. Apart from its involvement in two lymphoproliferative disorders, KSHV plays a vital role in the development of Kaposi sarcoma, the most common form of cancer in patients with AIDS (1, 2). After a primary infection event, the virus establishes lifelong latent persistence in the nuclei of its host cells. A molecular key player in the establishment, maintenance, and regulation of KSHV latency is the latency-associated nuclear antigen (LANA).KSHV LANA contains 1,162 amino acids in the prototype strain and exerts functions in host cell survival, transcriptional control, latent viral replication, and stable episome segregation during mitosis (3,4). Its N-terminal domain is separated from its C-terminal domain by a large internal repeat region (5, 6). Although the N-terminal domain and the internal repeat region are predicted to be only poorly structured (7), the C-terminal domain comprises a stable 3D structure with a strong hydrophobic core (8, 9). LANA's C-terminal domain binds to the LANA binding sites (LBS) within the viral terminal repeats (TRs) in a sequence-specific manner (10, 11). Therefore, this domain is referred to as the DNA-binding domain (DBD). In contrast, the N terminus of LANA binds to nucleosome...

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Section: The Lana Dbd Exhibits Two Dna-binding Modesmentioning

confidence: 99%

The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

Hellert

Weidner-Glunde

Krausze

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

149

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“…Replication factor C, the DNA polymerase clamp (proliferating cell nuclear antigen (PCNA)) loader allows processive DNA replication and is recruited to TR DNA by direct interaction with LANA to mediate replication. However, LANA residues 262-320, rather than the C-terminal domain, are critical for replication factor C interaction (63). Topoisomerase II␤, which facilitates DNA replication by inducing double stranded breaks, interacts with LANA N-terminal amino acids 1-32 and not the C-terminal domain (64).…”

Section: Discussionmentioning

confidence: 99%

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

Tan

Juillard

et al. 2015

Journal of Biological Chemistry

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Background: KSHV LANA binds virus DNA to mediate episome maintenance. Results: Mutating the novel LANA DNA binding domain (DBD) positive electrostatic patch engenders replication and episome persistence deficiencies. Conclusion: The LANA positive patch, possibly acting through a cell partner, is important for episome maintenance. Significance: Strategies that interfere with LANA positive patch function may allow future disruption of KSHV latency.

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“…Proteomic profiling of EBV EBNA1 by AP-LC-MS/MS defined protein interactions in EBV-associated cancers in both latent and lytic infection (56). Similar studies using KSHV LANA, showed that the RFC complex interacted with LANA and is important for viral replication (57). Another study defined cellular proteins that interacted with LANA, and determined which of these interactions were mediated through the LANA SUMO Interacting motif (SIM) (58).…”

Section: Molecular and Cellular Proteomics 16 Supplement 4 S67mentioning

confidence: 93%

The Promise of Proteomics in the Study of Oncogenic Viruses

McBride

2017

Molecular & Cellular Proteomics

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Oncogenic viruses are responsible for about 15% human cancers. This article explores the promise and challenges of viral proteomics in the study of the oncogenic human DNA viruses, HPV, McPyV, EBV and KSHV. These viruses have coevolved with their hosts and cause persistent infections. Each virus encodes oncoproteins that manipulate key cellular pathways to promote viral replication and evade the host immune response. Viral proteomics can identify cellular pathways perturbed by viral infection, identify cellular proteins that are crucial for viral persistence and oncogenesis, and identify important diagnostic and therapeutic targets.

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Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Cited by 44 publications

References 50 publications

The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

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

The Promise of Proteomics in the Study of Oncogenic Viruses

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