University of Toronto Biochemistry

	Alexander Palazzo Assistant Professor B.Sc., McGill University, 1997 Ph.D., Columbia University, 2003 PDF, Harvard Medical School, 2003-2009
	Medical Sciences Building, Room 5336 416-978-7234 alex.palazzo@utoronto.ca

Mechanisms of mRNA Nuclear Export and Localization

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Research Synopsis

Gene expression plays a critical role in regulating and modifying various cellular functions, which impact on processes such as development and homeostasis. Gene activation begins in the nucleus, where DNA is transcribed into a nascent transcript that is processed so that non-coding introns are removed by the splicesome, and a cap and poly(A)-tail are added to the beginning and end of the RNA, respectively. Once processing is complete, the mature messenger RNA (mRNA) is exported to the cytoplasm where it localizes to distinct subcellular sites. For example in higher eukaryotes, it is believed that mRNAs coding for secreted and membrane bound proteins are targeted to the surface of the endoplasmic reticulum (ER) primarily through information contained within the transcript's encoded protein and are maintained on the ER through the translating ribosome.

My lab utilizes sophisticated cell manipulation protocols, in order to
figure out:

1) How are mRNAs exported from the nucleus?
2) How are mRNAs localized to their proper subcellular destination?

We have discovered specialized pathways that promote the export of certain
classes of transcripts, those that code for secreted proteins and contain a signal sequence coding region (SSCR), and those that contain a mitochondrial targeting sequence coding region (MSCR). Our data indicates that these RNA elements recruit specialized factors in the nucleus which promote not only export but also the the proper localization of the mRNA to specialized subcellular sites in the cytoplasm, such as the ER.

In other work we have demonstrated that mRNAs coding for secretory and membrane bound proteins can associate with the ER independently of translation. Our results indicate that RNA elements promote the targeting and maintenance of certain transcripts onto the ER and that these pathways may act in conjunction with the translation dependent pathway to ensure the fidelity of proper protein sorting to the secretory pathway.

Our long term goal is to understand how these various mRNA export and
localization pathways contribute to cellular organization and gene expression.

Selected Publications

Palazzo, A.F. and Gregory, T.R. The case for junk DNA. PLoS Genetics in press.

Cui, X.A. and Palazzo, A.F. Localization of mRNAs to the endoplasmic
reticulum. WIREs RNA, 2014, doi: 10.1002/wrna.1225. [Epub ahead of print].

Cui, X.A., Zhang, Y., Seo, J.H., and Palazzo, A.F. Identification of an RNA Element that Mediates the p180-Dependent Targeting of mRNA to the Endoplasmic Reticulum. JBC, 2013, 288(41):29633-29641.

Akef, A., Zhang, H., Masuda, S., and Palazzo, A.F. Trafficking of mRNAs containing ALREX- promoting elements through nuclear speckles. Nucleus, 2013, 4(4): 326-40.

Palazzo, A.F., Kohila, K.M., and Tarnawsky, S.P. ALREX-elements and introns: two identity elements that promote mRNA nuclear export. WIREs RNA, 2013, 4(5): 523-533.

Mahadevan, K., Zhang, H., Akef A., Cui, X.A., Gueroussov S., Cenik, C., Roth F.P. and Palazzo, A.F. RanBP2/Nup358 Potentiates the Translation of a Subset of mRNAs Encoding Secretory Proteins. PLoS Biology 2013, 11(4): e1001545.

Cui, X.A. and Palazzo, A.F. Visualization of Endoplasmic Reticulum Localized mRNAs in Mammalian Cells. J. Vis. Exp. 2012, 70:e50066.

Cui, X.A., Zhang, H., and Palazzo, A.F. p180 Promotes the Ribosome-Independent Association of a Subset of mRNA to the Endoplasmic Reticulum. PLoS Biology 2012, 10(5): e1001336.

Tarnawsky, S.P., and Palazzo, A.F., Positional Requirements for the Stimulation of mRNA Nuclear Export by ALREX-Promoting Elements. Molecular BioSystems 2012, 8(10):2527-30.

Palazzo, A.F., and Akef, A., Nuclear Export as a Key Arbiter of "mRNA Identity" in Eukaryotes. Biochim Biophys Acta 2012, 1819(6):566-77.

Palazzo, A.F., and Mahadevan, K., Alternative Splicing Rewires Cell Metabolism to Turn on the Warburg Effect. Biomedical Research 2012, 23 SI:17-23.

Cenik, C., Chua, H.N., Zhang, H, Tarnawsky, S., Akef, A., Derti, A., Tasan, M., Moore, M.J., Palazzo, A.F.*, and Roth, F.P.* Genome analysis reveals interplay between 5'UTR introns and nuclear mRNA export for secretory and mitochondrial genes. PLoS Genetics 2011, 7(4): e1001366. *co-corresponding authors.

Gueroussov, S., Tarnawsky, S.P., Cui, X.A., Mahadevan, K. and Palazzo, A.F. Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection. J Vis Exp. 2010, 46:2387.

Shibata, Y., Shemesh, T., Prinz, W.A., Palazzo, A.F., Kozlov, M.M.and Rapoport, T.A. Mechanisms determining the morphology of the peripheral ER. Cell 2010 143(5):774-88.

Palazzo, A.F., Springer, M., Shibata, Y., Lee, C.S., Dias, A.P. and Rapoport, T.A. The Signal Sequence Coding Region Promotes Nuclear Export of mRNA. PLoS Biology 2007, 5(12): e322.

Palazzo, A.F., Eng, C.H., Schlaepfer, D.D., Marcantonio, E.E. and Gundersen,
G.G. Localized Stabilization of Microtubules By Integrin Facilitated Rho Signaling. Science 2004, 303:836-839.

Palazzo A.F., Ackerman B. and Gundersen G.G. Tubulin acetylation and cell motility. Nature 2003, 421:230.

Palazzo A.F. and Gundersen, G. G. Microtubule-actin crosstalk at focal adhesions. Science Signaling 2002, 139:PE31.

Palazzo A.F., Joseph H.L., Chen Y.J., Dujardin D.L., Alberts A., Pfister K.K., Vallee R.B. and Gundersen G.G. Cdc42, dynein and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr Biol 2001, 11: 1536-1541.

Palazzo A.F., Cook T.A., Alberts A. and Gundersen G.G. mDia mediates Rho-regulated formation and orientation of stable microtubules. Nat Cell Biol 2001, 3: 723-729.

Department of Biochemistry
University of Toronto
Toronto, Canada

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