This is an ongoing project headed by Dr. DiMaio. Senescence is an important tumor suppressor mechanism. Not only does senescence appear to prevent tumor formation in vivo, but it may be possible to mobilize a durable senescence response as a new approach to treat cancer. With the support of this grant, we have developed a new model of cellular senescence induced by transcriptional repression of the human papillomavirus oncogenes in cervical carcinoma cell lines. In contrast to most other models of senescence, senescence induced by HPV repression is rapid, uniform, and synchronous. We will use this model to explore two important aspects of senescence. First, we will determine the molecular mechanism by which the initial growth arrest caused by HPV E7 repression is converted to an irreversible senescent state. We will test the hypothesis that the stable assembly of heterochromatin at repressed promoters is the primary cause of irreversibility. We will use this system to determine how this ~epressive heterochromatin is formed, and we will conduct a genetic screen to identify cellular genes with the ability to either reverse senescence on their own or to cooperate with re-expressed viral oncogenes to reverse senescence. Second, we will conduct a comprehensive genetic and biochemical analysis of the role of cellular microRNAs in determining the senescence phenotype and the pattern of cellular gene expression in senescent cells. In collaboration with Dr. Steitz, we will compare microRNAs activity in two different growth-arrested states, senescence and quiescence. Taken together, these experiments will provide new insights into the molecular mechanisms that establish and maintain the senescent state, and may set the stage for attempts to translate this knowledge into rational new approaches to treat or prevent cancer by modulating the senescence response.

Public Health Relevance

Senescence is an important cellular process that prevents tumor formation and is being explored as a potential new approach to cancer therapy. We are determining the molecular mechanisms that are responsible for the long-term growth arrest that defines senescence, and are exploring the regulatory gene circuits that are responsible for this phenomenon. A better understanding of senescence will allow us to manipulate this process to prevent or treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA016038-40
Application #
8476992
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
40
Fiscal Year
2013
Total Cost
$285,953
Indirect Cost
$111,239
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Pengwei; Monteiro da Silva, Gabriel; Deatherage, Catherine et al. (2018) Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human Papillomavirus L2 Protein to Trigger Retrograde Trafficking. Cell 174:1465-1476.e13
Inoue, Takamasa; Zhang, Pengwei; Zhang, Wei et al. (2018) ?-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection. J Cell Biol 217:3545-3559
Vallery, Tenaya K; Withers, Johanna B; Andoh, Joana A et al. (2018) Kaposi's Sarcoma-Associated Herpesvirus mRNA Accumulation in Nuclear Foci Is Influenced by Viral DNA Replication and Viral Noncoding Polyadenylated Nuclear RNA. J Virol 92:
Hayes, Karen E; Barr, Jamie A; Xie, Mingyi et al. (2018) Immunoprecipitation of Tri-methylated Capped RNA. Bio Protoc 8:
Park, Richard; Miller, George (2018) Epstein-Barr Virus-Induced Nodules on Viral Replication Compartments Contain RNA Processing Proteins and a Viral Long Noncoding RNA. J Virol 92:
Lipovsky, Alex; Erden, Asu; Kanaya, Eriko et al. (2017) The cellular endosomal protein stannin inhibits intracellular trafficking of human papillomavirus during virus entry. J Gen Virol 98:2821-2836
Singh, Gatikrushna; Fritz, Sarah M; Ranji, Arnaz et al. (2017) Isolation of Cognate RNA-protein Complexes from Cells Using Oligonucleotide-directed Elution. J Vis Exp :
Martinez, Ivan; Hayes, Karen E; Barr, Jamie A et al. (2017) An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence. Proc Natl Acad Sci U S A 114:E4961-E4970
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
Gorres, Kelly L; Daigle, Derek; Mohanram, Sudharshan et al. (2016) Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus. MBio 7:e00113

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