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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-GRB-S)
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Yale University
New Haven
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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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