The roles of non-coding RNAs in lymphoid cells harboring three transforming herpesviruses are being investigated. Epstein-Barr virus (EBV) infects and transforms humanB cells;it is the causative agent of infectious mononucleosis and is associated with several human cancers. Herpesvirus saimiri (HVS) induces fatal lymphomas and leukemias in New World monkeys and transforms human and monkey T lymphocytes in culture, generating a mature;activated phenotype. Kaposi's sarcoma-associated herpesvirus (KSHV) afflicts immunocompromised individuals and persists in a latent form until lytic activation. The two EBVencoded EBERs, as well as >23 newly identified microRNAs, and the seven HVS-encoded HSURs are expressed in virally transformed cells. Upon induction, KSHV produces PAN, a capped, polyadenylated RNA that does not leave the nucleus. These viral RNAs are all small (from 21 nts to 1.1 kb), abundant, conserved, and associate with host proteins to form RNPs. Studying their functions has,already contributed important insights into host cell pathways perturbed during viral transformation or lytic growth. Proposed aims will test the hypotheses that EBERs, HSURs and PAN manipulate cellular metabolism by sequestering host proteins or microRNAs, or that the resulting RNPs perform a critical viral function. We recently found that HSUR RNPs bind certain host microRNAs;interference with their regulatory roles in transformed T cells will be examined. The possibility that EBERs likewise bind host microRNAs will be tested. Our discovery that microRNAs in quiescent cells activate rather than repress translation will be exploited to investigate the EBV-encoded microRNAs since many transformed B cells exist in a quiescent state in the body. We showed that PAN RNA accumulates to very high nuclear levels in KSHV-reactivated cells because an element (the ENE) near its 3'end engages the polyA tail to prevent RNA decay. Structural studies of the ENE +/- oligoA, as well as complexed with polyA binding protein (PABPC1), will provide mechanistic insights. Our observation that PAN RNA is involved in relocalization of host PABPC1 to the nucleus, suggesting collaboration with the KSHV SOX protein in host mRNA shut off, will be investigated

Public Health Relevance

We are studying how viruses that cause lymphomas or sarcomas in humans or monkeys use RNA molecules to manipulate their host cells to the advantage of the virus. These RNAs are not messages for proteins but act to alter how other genes function after infection. Understanding these viral non-coding RNAs will provide novel targets for the design of therapeutics to combat these cancer-causing viruses.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Yale University
New Haven
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Luo, Yong; Motamedi, Nasim; Magaldi, Thomas G et al. (2016) Interaction between Simian Virus 40 Major Capsid Protein VP1 and Cell Surface Ganglioside GM1 Triggers Vacuole Formation. MBio 7:e00297
Gorres, Kelly L; Daigle, Derek; Mohanram, Sudharshan et al. (2016) Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus. MBio 7:e00113
Brown, Jessica A; Kinzig, Charles G; DeGregorio, Suzanne J et al. (2016) Hoogsteen-position pyrimidines promote the stability and function of the MALAT1 RNA triple helix. RNA 22:743-9
Zhang, Wei; Xie, Mingyi; Shu, Mei-Di et al. (2016) A proximity-dependent assay for specific RNA-protein interactions in intact cells. RNA 22:1785-1792
Pawlica, Paulina; Moss, Walter N; Steitz, Joan A (2016) Host miRNA degradation by Herpesvirus saimiri small nuclear RNA requires an unstructured interacting region. RNA 22:1181-9
DiMaio, Daniel (2016) Thank You, Edward. Merci, Louis. PLoS Pathog 12:e1005320
Lee, Nara; Yario, Therese A; Gao, Jessica S et al. (2016) EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. Proc Natl Acad Sci U S A 113:3221-6
Tycowski, Kazimierz T; Shu, Mei-Di; Steitz, Joan A (2016) Myriad Triple-Helix-Forming Structures in the Transposable Element RNAs of Plants and Fungi. Cell Rep 15:1266-76
Brown, Jessica A; Kinzig, Charles G; DeGregorio, Suzanne J et al. (2016) Methyltransferase-like protein 16 binds the 3'-terminal triple helix of MALAT1 long noncoding RNA. Proc Natl Acad Sci U S A 113:14013-14018
Guo, Yang Eric; Oei, Theresa; Steitz, Joan A (2015) Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators. J Virol 89:10901-11

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