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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA016038-39
Application #
8380153
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
39
Fiscal Year
2012
Total Cost
$315,164
Indirect Cost
$122,605
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
DiMaio, Daniel (2016) Thank You, Edward. Merci, Louis. PLoS Pathog 12:e1005320
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
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
Gorres, Kelly L; Daigle, Derek; Mohanram, Sudharshan et al. (2016) Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus. MBio 7:e00113
McKenzie, Jessica; Lopez-Giraldez, Francesc; Delecluse, Henri-Jacques et al. (2016) The Epstein-Barr Virus Immunoevasins BCRF1 and BPLF1 Are Expressed by a Mechanism Independent of the Canonical Late Pre-initiation Complex. PLoS Pathog 12:e1006008
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
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
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
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

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