Photo of Kenneth M. Kaye,  MD

Kenneth M. Kaye, MD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-4256
Fax: (617) 525-4251


kkaye@rics.bwh.harvard.edu

Kenneth M. Kaye, MD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Associate Physician, Channing Laboratory, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory investigates the link between herpesviruses and human malignancy. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is linked with Kaposi's sarcoma, body cavity-based lymphomas and multicentric Castleman's disease, a lymphoproliferative disorder. Our goal is to gain a better understanding of the molecular mechanisms by which KSHV exerts tumorigenic effects.


KSHV infection in tumor cells is primarily latent. In latently infected cells, KSHV persists as a multiple copy plasmid (episome). In order to persist in proliferating cells, KSHV episomes must replicate and efficiently segregate to progeny cells. The KSHV latency-associated nuclear antigen (LANA) is expressed in KSHV infected tumor cells. We have shown that LANA colocalizes with KSHV episomes on chromosomes of KSHV infected cells. In addition, LANA is necessary and sufficient to mediate persistence of episomal DNA containing a specific KSHV sequence. These data are consistent with a model in which LANA tethers KSHV episomes to chromosomes during mitosis to ensure efficient segregation of KSHV DNA to progeny cells. We are presently investigating the molecular mechanisms by which LANA serves this function.

Publications

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  • Safavieh M, Khetani S, Juillard F, Kaul V, Kanakasabapathy MK, Kaye KM, Shafiee H. Electrical response of a B lymphoma cell line latently infected with Kaposi's sarcoma herpesvirus. Biosens Bioelectron 2016; 80:230-6. PubMed
  • Li S, Tan M, Juillard F, Ponnusamy R, Correia B, Simas JP, Carrondo MA, McVey CE, Kaye KM. The Kaposi Sarcoma Herpesvirus Latency-associated Nuclear Antigen DNA Binding Domain Dorsal Positive Electrostatic Patch Facilitates DNA Replication and Episome Persistence. J Biol Chem 2015. PubMed
  • Ponnusamy R, Petoukhov MV, Correia B, Custodio TF, Juillard F, Tan M, Pires de Miranda M, Carrondo MA, Simas JP, Kaye KM, Svergun DI, McVey CE. KSHV but not MHV-68 LANA induces a strong bend upon binding to terminal repeat viral DNA. Nucleic Acids Res 2015. PubMed
  • Inci F, Filippini C, Baday M, Ozen MO, Calamak S, Durmus NG, Wang S, Hanhauser E, Hobbs KS, Juillard F, Kuang PP, Vetter ML, Carocci M, Yamamoto HS, Takagi Y, Yildiz UH, Akin D, Wesemann DR, Singhal A, Yang PL, Nibert ML, Fichorova RN, Lau DT, Henrich TJ, Kaye KM, Schachter SC, Kuritzkes DR, Steinmetz LM, Gambhir SS, Davis RW, Demirci U. Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE2RD) for diagnostics. Proc Natl Acad Sci U S A 2015; 112:E4354-63. PubMed
  • Sun Q, Tsurimoto T, Juillard F, Li L, Li S, De León Vázquez E, Chen S, Kaye K. Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence. Proc Natl Acad Sci U S A 2014; 111:11816-21. PubMed
  • Beauchemin C, Moerke NJ, Faloon P, Kaye KM. Assay Development and High-Throughput Screening for Inhibitors of Kaposi's Sarcoma-Associated Herpesvirus N-Terminal Latency-Associated Nuclear Antigen Binding to Nucleosomes. J Biomol Screen 2014. PubMed
  • De León Vázquez E, Juillard F, Rosner B, Kaye KM. A short sequence immediately upstream of the internal repeat elements is critical for KSHV LANA mediated DNA replication and impacts episome persistence. Virology 2013; 448:344-55. PubMed
  • Vázquez Ede L, Carey VJ, Kaye KM. Identification of Kaposi's sarcoma-associated herpesvirus LANA regions important for episome segregation, replication, and persistence. J Virol 2013; 87:12270-83. PubMed
  • Correia B, Cerqueira SA, Beauchemin C, Pires de Miranda M, Li S, Ponnusamy R, Rodrigues L, Schneider TR, Carrondo MA, Kaye KM, Simas JP, McVey CE. Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. PLoS Pathog. 2013; 9:e1003673. PubMed
  • Rodrigues L, Popov N, Kaye KM, Simas JP. Stabilization of Myc through heterotypic poly-ubiquitination by mLANA is critical for γ-herpesvirus lymphoproliferation. PLoS Pathog. 2013; 9:e1003554. PubMed
  • Habison AC, Beauchemin C, Simas JP, Usherwood EJ, Kaye KM. Murine gammaherpesvirus 68 LANA acts on terminal repeat DNA to mediate episome persistence. J Virol 2012; 86:11863-76. PubMed
  • Kelley-Clarke B,De Leon-Vazquez E,Slain K,Barbera AJ,Kaye KM. Role of Kaposi's sarcoma-associated herpesvirus C-terminal LANA chromosome binding in episome persistence. J Virol 2009; 83:4326-37. PubMed
  • Chodaparambil JV, Barbera AJ, Lu X, Kaye KM, Hansen JC, Luger K. A charged and contoured surface on the nucleosome regulates chromatin compaction. Nat Struct Mol Biol 2007; 14:1105-7. PubMed
  • Bihl F, Narayan M, Chisholm JV, Henry LM, Suscovich TJ, Brown EE, Welzel TM, Kaufmann DE, Zaman TM, Dollard S, Martin JN, Wang F, Scadden DT, Kaye KM, Brander C. Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes. J Virol 2007; 81:4904-8. PubMed
  • Kelley-Clarke B, Ballestas ME, Srinivasan V, Barbera AJ, Komatsu T, Harris TA, Kazanjian M, Kaye KM. Determination of Kaposi's sarcoma-associated herpesvirus C-terminal latency-associated nuclear antigen residues mediating chromosome association and DNA binding. J Virol 2007; 81:4348-56. PubMed
  • Kelley-Clarke B, Ballestas ME, Komatsu T, Kaye KM. Kaposi's sarcoma herpesvirus C-terminal LANA concentrates at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes. Virology 2006; 357:149-57. PubMed
  • You J, Srinivasan V, Denis GV, Harrington WJ, Ballestas ME, Kaye KM, Howley PM. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 2006; 80:8909-19. PubMed
  • Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Luger K, Kaye KM. Kaposi's sarcoma-associated herpesvirus LANA hitches a ride on the chromosome. Cell Cycle 2006; 5:1048-52. PubMed
  • Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, Kaye KM. The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 2006; 311:856-61. PubMed
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