The broad long-term objective of the proposed research is to determine how aberrant base excision repair (BER) is linked to cancer.
The Specific Aims of this project are: 1. To test the hypothesis that cellular transforming activity is a common property of the Pol ~ cancerassociated variants. We will focus on variants we have not yet characterized and complete the characterization of interesting Pol ~ tumor-associated variants. We will use a combined genetic, biochemical and cell biological approach to identify the mechanism of cellular transformation that is employed by the variants. 2. To test the hypothesis that cancer-associated variants induce tumorigenesis in mice. "Knock-in" mice will be constructed using standard methods. Tumorigenesis will be monitored as a function of age and also in the presence of one or more DNA damaging agents. 3. To test the hypothesis that a combination of aberrant BER and viral infection leads to tumorigenesis. The mice constructed in Aim 3 will be used in a skin model of HPV to determine if viral proteins synergize with aberrant BER to decrease the rate or latency or increase the rate of tumorigenesis or metastasis. Various other mice with deficiencies in BER will also be characterized in this aim. 4. To test the hypothesis that microRNAs are important in the regulation of BER. To test the hypothesis that alterations in microRNA target sites in BER genes results in aberrant BER that is linked to cancer. We will characterize known germ line single nucleotide polymorph isms in conserved micro RNA target sites within the 3'UTRs of specific BER genes. We will also determine if microRNA targets are altered in human tumors.
BER is the guardian of the genome. In the previous funding period, we showed that aberrant BER that results from variant forms of Pol ~ found in tumors is linked to cancer. In the next funding period, we will examine specific mechanisms regarding the role of Pol ~ variants in inducing cellular transformation. We will also determine if aberrant BER synergizes with viral genes to promote carcinogenesis. These studies have the potential to provide mechanistic insight into the link between aberrant BER viruses and cancer.
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|Cech, Thomas R; Steitz, Joan A (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157:77-94|
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|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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