This is a renewal application for years 36 to 40 of a laboratory-based, interdisciplinary Program Project Grant, Molecular Basis of Viral and Cellular Transformation. For the last 15 years, this grant has been led by Daniel DiMaio, M.D., Ph.D., Waldemar Von Zedtwitz Professor of Genetics, and he continues as Principal Investigator. He is joined by three other project leaders: George Miller, Joan Steitz, and Joann Sweasy. All four project leaders have independent grant support from the NIH and have made major contributions to our understanding of virology and cell transformation. This Program seeks to achieve molecular understanding of the impact of viral and cellular gene products on cell transformation, because such understanding will provide insight into the genesis of cancer in humans and may suggest new approaches to therapy. In the past funding period, these same four project leaders participated in the Program, which resulted in 49 published papers, 37 of which are in top, peer-reviewed journals. These investigators will carry out five innovative, collaborative projects studying the molecular mechanisms by which viral and cellular gene products induce and maintain cellular transformation. Dr. Miller will study the switch from latency to lytic growth of Epstein-Barr virus, a major human carcinogen. Dr. DiMaio will study cellular senescence induced by repression of human papillomavirus oncogenes in cervical cancer cells, focusing on the molecular basis of the irreversible nature of senescence and on the role of microRNAs in senescence. In a separate project, he will determine the role of DNAJ proteins in SV40 infection. Dr. Steitz will study the role of tumor virus-encoded small RNAs in cell transformation. Dr. Sweasy will study the ability of cancer-associated DNA polymerase beta mutants to induce cellular transformation, with a focus on truncation mutants, animal models of carcinogenesis, and cooperation with human papillomavirus oncogenes. These projects will be supported by a small Administrative Core and an expanded Scientific Core. Several mechanisms are in place to ensure the cohesion of the program, including monthly meetings of the project leaders, an annual retreat, and boards of distinguished external and internal advisors to provide guidance and advice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (M1))
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Read-Connole, Elizabeth Lee
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Yale University
Schools of Medicine
New Haven
United States
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Guo, Yang Eric; Steitz, Joan A (2014) 3'-Biotin-tagged microRNA-27 does not associate with Argonaute proteins in cells. RNA 20:985-8
Goodwin, Edward C; Motamedi, Nasim; Lipovsky, Alex et al. (2014) Expression of DNAJB12 or DNAJB14 causes coordinate invasion of the nucleus by membranes associated with a novel nuclear pore structure. PLoS One 9:e94322
Cech, Thomas R; Steitz, Joan A (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157:77-94
Dimaio, Daniel (2014) Is virology dead? MBio 5:e01003-14
Guo, Yang Eric; Riley, Kasandra J; Iwasaki, Akiko et al. (2014) Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function. Mol Cell 54:67-79
Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47
Zhang, Wei; Kazakov, Teymur; Popa, Andreea et al. (2014) Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires ?-secretase activity. MBio 5:e01777-14
Xie, Mingyi; Steitz, Joan A (2014) Versatile microRNA biogenesis in animals and their viruses. RNA Biol 11:673-81
Park, Richard; El-Guindy, Ayman; Heston, Lee et al. (2014) Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. PLoS One 9:e92593
Guo, Yang Eric; Steitz, Joan A (2014) Virus meets host microRNA: the destroyer, the booster, the hijacker. Mol Cell Biol 34:3780-7

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