Overview: Our work has revealed a previously unidentified RNA-protein interaction that is necessary for translation of complex mRNAs. Our studies implicate RNA helicase A as an integrative effector of gene expression that is involved in the continuum from transcription to translation in cells, and in viruses.
Translational Control of Unspliced of Retroviruses and their Host Cell: Retroviruses vary widely in their ability to cause neoplastic transformation, immunodeficiency, but also can function as nonpathogenic vectors for gene transfer applications. A shared characteristic among retroviruses is the need to recruit host cell proteins to direct translation of their unspliced genome-length precursor-mRNA. We have identified a novel RNA element in several retroviruses that is essential for efficient translation of the unspliced pre-mRNA. The element, which is designated the post-transcriptional control element (PCE), is positioned at the 5' end of the pre-mRNA and recruits a host cell protein of the DEAD box superfamily, RNA helicase A. Together PCE/RNA helicase A overcome a gauntlet of structural barriers to ribosome scanning that are poised between the 5' end of the transcript and the translation start codon to facilitate efficient translation initiation. View the model for PCE activity.
By analysis of a broad array of retroviral and cellular genes, we have determined that a several of lymphotropic retroviruses and cellular genes use PCE/RNA helicase A interaction to modulate translation. For example, PCE/ RNA helicase A activity is necessary for translation of junD, an important growth control gene that is a component of the AP-1 transcription factor.
Ongoing experiments are characterizing additional retroviral and cellular genes that require PCE/ RNA helicase A for their efficient translation. Our long-term goal is to understand the mechanism of the specialized translational control axis that is operated by PCE/ RNA helicase A. Furthermore, to characterize the role of PCE/ RNA helicase A in selectively fine-tuning cellular gene expression, both in healthy cells and in cancer and other diseases.
Selected publications from the lab
- Hartman, T. R., Qian, S., Fernandez, S., Schoenberg, D.R., and Boris-Lawrie, K. 2006. RNA helicase A stimulates translation of selected mRNAs. Nature Structural and Molecular Biology 13, 509 – 516. doi May 6. 2006.
- Yilmaz, A., Fernandez, S., Lairmore, M.D, Boris-Lawrie, K. 2006. Coordinated enhancement of transgene transcription and translation in a lentiviral vector. Retrovirology 3:13.
- Yilmaz, A., Bolinger, C., Boris-Lawrie, K. 2006. Retrovirus translation initiation: Issues and hypotheses derived from study of HIV-1. Current HIV Research 4:131-139.
- Altanerova, V., Holicova, D., Kucerova, L., Altaner, C., Boris-Lawrie, K. 2004. Long-term infection with bovine leukemia virus structural gene vector provides protection against BLV disease in rabbits. Virology 329:434-439.
- Hull, S. and Boris-Lawrie, K. 2003. Analysis of synergy between divergent simple retrovirus posttranscriptional control elements. Virology 317(1):146-154.
- Roberts, T. M. and Boris-Lawrie, K.2003. Primary sequence and secondary structure motifs in spleen necrosis virus RU5 confer translational utilization of unspliced HIV-1 reporter RNA". Journal of Virology 77(22):11973-11984.
- Hull, S. and K. Boris-Lawrie. 2002. The RU5 region of the Mason-Pfizer monkey virus 5' LTR facilitates cytoplasmic expression of retroviral and nonviral reporter RNA. Journal of Virology 76 (20):10211-10218.
- Dangel, A. S. Hull, T. Roberts, and K. Boris-Lawrie. 2002. Nuclear interactions are necessary for translational enhancement by SNV PCE. Journal of Virology 76 (7):3292-3300.
- Butsch, M. and K. Boris-Lawrie. 2002. The destiny of retroviral unspliced RNA: ribosome or virion? Journal of Virology 76 (7): 3089-3094.
- Boris-Lawrie, K., T. Roberts, S. Hull. 2001. Retroviral RNA elements integrate components of post-transcriptional gene expression. Life Sciences 69:2697-2709.
- Altaner, C., V. Altanerova, D. Holicova, K. Boris-Lawrie. 2001. Structural gene vector infection protects rabbits from bovine leukaemia virus challenge. AIDS and Human Retroviruses 17(1):O31.
- Butsch, M. and K. Boris-Lawrie. 2000. Translation is not necessary to generate virion precursor RNA in human immunodeficiency virus type 1 infected T-cells. Journal of Virology 74(24):11531-11537.
- Roberts, T.M. and K. Boris-Lawrie. 2000. RU5 of spleen necrosis virus is a stimulatory sequence that enhances translation of nonviral reporter gene mRNA. Journal of Virology 74(17):8111-8118.
- Kucerova, L., V. Altanerova, C. Altaner, K. Boris-Lawrie. 1999. Bovine leukemia virus structural gene vectors are immunogenic and lack pathogenicity in a rabbit model. Journal of Virology 73 (10):8160-8166.
- Butsch, M., S. Hull, Y. Wang, T.M. Roberts, K. Boris-Lawrie. 1999. The 5' RNA terminus of spleen necrosis virus contains a novel post-transcriptional control element that facilitates human immunodeficiency virus Rev/RRE-independent Gag production. Journal of Virology 73(6): 4847-4855.