Molecular Basis for Oligomeric-DNA Binding and Episome Maintenance by KSHV LANA

LANA is the KSHV-encoded terminal repeat binding protein essential for viral replication and episome maintenance during latency. We have determined the X-ray crystal structure of LANA C-terminal DNA binding domain (LANADBD) to reveal its capacity to form a decameric ring with an exterior DNA binding surface. The dimeric core is structurally similar to EBV EBNA1 with an N-terminal arm that regulates DNA binding and is required for replication function. The oligomeric interface between LANA dimers is dispensable for single site DNA binding, but is required for cooperative DNA binding, replication function, and episome maintenance. We also identify a basic patch opposite of the DNA binding surface that is responsible for the interaction with BRD proteins and contributes to episome maintenance function. The structural features of LANADBD suggest a novel mechanism of episome maintenance through DNA-binding induced oligomeric assembly.

[1]  R. Tsien,et al.  A Structural Basis for the Assembly and Functions of a Viral Polymer that Inactivates Multiple Tumor Suppressors , 2012, Cell.

[2]  Jun Wan,et al.  Phosphorylation of the Chromatin Binding Domain of KSHV LANA , 2012, PLoS pathogens.

[3]  T. Schulz,et al.  The Ubiquitin-Specific Protease USP7 Modulates the Replication of Kaposi's Sarcoma-Associated Herpesvirus Latent Episomal DNA , 2012, Journal of Virology.

[4]  R. Davuluri,et al.  Identification of Host-Chromosome Binding Sites and Candidate Gene Targets for Kaposi's Sarcoma-Associated Herpesvirus LANA , 2012, Journal of Virology.

[5]  Shaohui Hu,et al.  A Protein Array Screen for Kaposi's Sarcoma-Associated Herpesvirus LANA Interactors Links LANA to TIP60, PP2A Activity, and Telomere Shortening , 2012, Journal of Virology.

[6]  M. Ballestas,et al.  The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latency. , 2011, Future microbiology.

[7]  Z. Weng,et al.  Mutational analysis of the latency-associated nuclear antigen DNA-binding domain of Kaposi's sarcoma-associated herpesvirus reveals structural conservation among gammaherpesvirus origin-binding proteins , 2010, The Journal of general virology.

[8]  S. Verma,et al.  Bub1 and CENP-F Can Contribute to Kaposi's Sarcoma-Associated Herpesvirus Genome Persistence by Targeting LANA to Kinetochores , 2010, Journal of Virology.

[9]  S. Tojkander,et al.  Nucleophosmin Phosphorylation by v-Cyclin-CDK6 Controls KSHV Latency , 2010, PLoS pathogens.

[10]  Satoko Matsumura,et al.  The Latency-Associated Nuclear Antigen Interacts with MeCP2 and Nucleosomes through Separate Domains , 2009, Journal of Virology.

[11]  Roberto Sanchez,et al.  The role of human bromodomains in chromatin biology and gene transcription. , 2009, Current opinion in drug discovery & development.

[12]  Shwu‐Yuan Wu,et al.  The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation* , 2007, Journal of Biological Chemistry.

[13]  M. Ballestas,et al.  Determination of Kaposi's Sarcoma-Associated Herpesvirus C-Terminal Latency-Associated Nuclear Antigen Residues Mediating Chromosome Association and DNA Binding , 2007, Journal of Virology.

[14]  T. Schulz,et al.  Kaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G1 Cell CycleArrest , 2006, Journal of Virology.

[15]  P. Lieberman,et al.  Acetylation of the Latency-Associated Nuclear Antigen Regulates Repression of Kaposi's Sarcoma-Associated Herpesvirus Lytic Transcription , 2006, Journal of Virology.

[16]  S. Verma,et al.  Latency-Associated Nuclear Antigen (LANA) of Kaposi's Sarcoma-Associated Herpesvirus Interacts with Origin Recognition Complexes at the LANA Binding Sequence within the Terminal Repeats , 2006, Journal of Virology.

[17]  K. Luger,et al.  The Nucleosomal Surface as a Docking Station for Kaposi's Sarcoma Herpesvirus LANA , 2006, Science.

[18]  S. Schuck,et al.  Assembly of a double hexameric helicase. , 2005, Molecular cell.

[19]  T. Schulz,et al.  Brd2/RING3 Interacts with a Chromatin-Binding Domain in the Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen 1 (LANA-1) That Is Required for Multiple Functions of LANA-1 , 2005, Journal of Virology.

[20]  Angus C. Wilson,et al.  Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Induces a Strong Bend on Binding to Terminal Repeat DNA , 2005, Journal of Virology.

[21]  E. Robertson,et al.  Kaposi's Sarcoma-Associated Herpesvirus Reactivation Is Regulated by Interaction of Latency-Associated Nuclear Antigen with Recombination Signal Sequence-Binding Protein Jκ, the Major Downstream Effector of the Notch Signaling Pathway , 2005, Journal of Virology.

[22]  Jianhong Hu,et al.  Characterization of the Minimal Replicator of Kaposi's Sarcoma-Associated Herpesvirus Latent Origin , 2005, Journal of Virology.

[23]  M. Ballestas,et al.  Definition of Sequence Requirements for Latency-Associated Nuclear Antigen 1 Binding to Kaposi's Sarcoma-Associated Herpesvirus DNA , 2004, Journal of Virology.

[24]  William Stedman,et al.  ORC, MCM, and Histone Hyperacetylation at the Kaposi's Sarcoma-Associated Herpesvirus Latent Replication Origin , 2004, Journal of Virology.

[25]  D. Gai,et al.  Mechanisms of Conformational Change for a Replicative Hexameric Helicase of SV40 Large Tumor Antigen , 2004, Cell.

[26]  S. Verma,et al.  Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Inhibits Lytic Replication by Targeting Rta: a Potential Mechanism for Virus-Mediated Control of Latency , 2004, Journal of Virology.

[27]  M. Ballestas,et al.  KSHV LANA1 binds DNA as an oligomer and residues N-terminal to the oligomerization domain are essential for DNA binding, replication, and episome persistence. , 2004, Virology.

[28]  Yuan Chang,et al.  The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts preferentially with the terminal repeats of the genome in vivo and this complex is sufficient for episomal DNA replication. , 2003, The Journal of general virology.

[29]  D. Ganem,et al.  The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Permits Replication of Terminal Repeat-Containing Plasmids , 2003, Journal of Virology.

[30]  Jianhong Hu,et al.  The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Supports Latent DNA Replication in Dividing Cells , 2002, Journal of Virology.

[31]  M. Fujimuro,et al.  Protein Interactions Targeting the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus to Cell Chromosomes , 2002, Journal of Virology.

[32]  C. Lim,et al.  Functional Dissection of Latency-Associated Nuclear Antigen 1 of Kaposi's Sarcoma-Associated Herpesvirus Involved in Latent DNA Replication and Transcription of Terminal Repeats of the Viral Genome , 2002, Journal of Virology.

[33]  Jianhong Hu,et al.  Latency-associated Nuclear Antigen (LANA) Cooperatively Binds to Two Sites within the Terminal Repeat, and Both Sites Contribute to the Ability of LANA to Suppress Transcription and to Facilitate DNA Replication* , 2002, The Journal of Biological Chemistry.

[34]  D. Dittmer,et al.  Charting Latency Transcripts in Kaposi's Sarcoma-Associated Herpesvirus by Whole-Genome Real-Time Quantitative PCR , 2002, Journal of Virology.

[35]  E. Robertson,et al.  The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen binds to specific sequences at the left end of the viral genome through its carboxy-terminus. , 2001, Virology.

[36]  J. Yates,et al.  Replication from oriP of Epstein-Barr Virus Requires Exact Spacing of Two Bound Dimers of EBNA1 Which Bend DNA , 2001, Journal of Virology.

[37]  Jianhong Hu,et al.  DNA Binding and Modulation of Gene Expression by the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus , 2001, Journal of Virology.

[38]  T. Piolot,et al.  Close but Distinct Regions of Human Herpesvirus 8 Latency-Associated Nuclear Antigen 1 Are Responsible for Nuclear Targeting and Binding to Human Mitotic Chromosomes , 2001, Journal of Virology.

[39]  M. Ballestas,et al.  Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen 1 Mediates Episome Persistence through cis-Acting Terminal Repeat (TR) Sequence and Specifically Binds TR DNA , 2001, Journal of Virology.

[40]  C. Lim,et al.  Latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) binds ATF4/CREB2 and inhibits its transcriptional activation activity. , 2000, The Journal of general virology.

[41]  G. Nabel,et al.  p53 inhibition by the LANA protein of KSHV protects against cell death , 1999, Nature.

[42]  T. Schulz,et al.  Latent Nuclear Antigen of Kaposi’s Sarcoma-Associated Herpesvirus Interacts with RING3, a Homolog of theDrosophila Female Sterile Homeotic (fsh) Gene , 1999, Journal of Virology.

[43]  E. Robertson,et al.  The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. , 1999, Virology.

[44]  M. Ballestas,et al.  Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. , 1999, Science.

[45]  E. Bochkareva,et al.  The 2.2 A structure of a permanganate-sensitive DNA site bound by the Epstein-Barr virus origin binding protein, EBNA1. , 1998, Journal of molecular biology.

[46]  P. Moore,et al.  TRANSCRIPTION MAPPING OF KSHV IN A BODY CAVITY-BASED LYMPHOMA CELL LINE (BC-1) , 1998 .

[47]  P. Moore,et al.  Transcription Mapping of the Kaposi’s Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Genome in a Body Cavity-Based Lymphoma Cell Line (BC-1) , 1998, Journal of Virology.

[48]  D. Ganem,et al.  The structure and coding organization of the genomic termini of Kaposi's sarcoma-associated herpesvirus. , 1997, Virology.

[49]  R. Pfuetzner,et al.  Cooperative assembly of EBNA1 on the Epstein-Barr virus latent origin of replication , 1996, Journal of Virology.

[50]  R. Pfuetzner,et al.  Crystal structure of the DNA-binding domain of the Epstein-Barr virus origin-binding protein EBNA1 , 1995, Cell.

[51]  F. Sigaux,et al.  Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. , 1995, Blood.

[52]  E. Cesarman,et al.  Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. , 1995, The New England journal of medicine.

[53]  E. Cesarman,et al.  Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. , 1994, Science.

[54]  L. Frappier,et al.  Stabilization of the EBNA1 protein on the Epstein-Barr virus latent origin of DNA replication by a DNA looping mechanism. , 1994, The Journal of biological chemistry.

[55]  S. Grossman,et al.  Crystal structure at 1.7 Å of the bovine papillomavirus-1 E2 DMA-binding domain bound to its DNA target , 1992, Nature.

[56]  G. Hayward,et al.  Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region , 1985, Cell.

[57]  S. Verma,et al.  Structure and function of latency-associated nuclear antigen. , 2007, Current topics in microbiology and immunology.

[58]  P. Lieberman,et al.  Maintenance and replication during latency , 2007 .

[59]  P. Moore,et al.  Maintenance and replication during latency -- Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis , 2007 .

[60]  P. Lieberman,et al.  Human Herpesviruses: Gammaherpesvirus maintenance and replication during latency , 2007 .

[61]  T. Schulz,et al.  The Kaposi ’ s Sarcoma-Associated Herpesvirus LANA-1 interacts with the short variant of BRD 4 1 and releases cells from a BRD 4-and BRD 2 / RING 3-induced G 1 cell cycle arrest . 2 3 4 , 2006 .

[62]  L. Szekely,et al.  Latent nuclear antigen of Kaposi's sarcoma herpesvirus/human herpesvirus-8 induces and relocates RING3 to nuclear heterochromatin regions. , 2002, The Journal of general virology.

[63]  C. Collins,et al.  Genetic requirements for the episomal maintenance of oncogenic herpesvirus genomes. , 2002, Advances in cancer research.

[64]  D. Lowy,et al.  Bovine papillomavirus E2 trans-activating gene product binds to specific sites in papillomavirus DNA , 1987, Nature.