L1 (Long Interspersed Nuclear Element 1) retrotransposons are the most active mobile elements in the human genome. They are present in over 500,000 copies. L1 insertions can disrupt gene function and add to the overall mass of the genome. Despite their abundance, very little is known about how Lls are regulated. In this proposal, I investigate three potential strategies used by mammalian cells to contain L1 damage to the genome: 1. Repair double stranded DNA breaks that are caused by or used for L1 insertions. 2. Kill cells with damaging L1 insertions by apoptosis. 3. Try to prevent L1 insertion by using RNA interference to destroy L1 RNA. To investigate these hypothesized modes of L1 regulation, my lab has developed a flow cytometric assay to monitor L1 retrotransposition in cultured cells. We have also created mice with green fluorescent protein tagged L1 transgenes. A better understanding of how L1 retrotransposition is regulated should yield important insights into L1 biology, mechanism and the potential of L1s to contribute to genomic instability in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108812-03
Application #
7109356
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Pelroy, Richard
Project Start
2004-08-16
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$253,831
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Farkash, Evan A; Kao, Gary D; Horman, Shane R et al. (2006) Gamma radiation increases endonuclease-dependent L1 retrotransposition in a cultured cell assay. Nucleic Acids Res 34:1196-204