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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA016038-39
Application #
8307760
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-05-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
39
Fiscal Year
2012
Total Cost
$1,519,324
Indirect Cost
$591,046
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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