Paula Grabowski

Professor

Alternative RNA splicing

Paula Grabowski
Office: (412) 624-6983
Lab: (412) 624-6984
A502A Langley Hall
4249 Fifth Avenue
Pittsburgh, PA 15260
Education

Dr. Grabowski received her Ph.D. in 1983 with Tom Cech at the University of Colorado, performed her postdoctoral studies with Philip Sharp at the Massachusetts Institute of Technology, and joined the Department in 1991.

Alternative splicing and its regulation

Why do human cells express more protein varieties than the genes encoding them? How did this mismatch arise, and is it biologically purposeful? The upshot is that alternative pre-mRNA splicing pathways are responsible for producing molecular decisions in the form of messenger RNA transcripts, which diversify the forms and functions of protein families encoded in the genome. Ultimately, the spliceosome is the biochemical gatekeeper of splicing decisions. It must be nimble in the way it directs decisions about splice site recognition to favor or disfavor one splicing pathway over another, while preserving accuracy. Splicing decisions can have a profound impact on cellular fate and behavior. In the nervous system for example, the inhibition of certain splicing pathways relative to others can automate the time course of differentiation of neuronal precursors into mature cells, whereas other mechanisms specify connectivity patterns and electrical properties of neurons. In many cell types, splicing decisions can indeed have a beneficial effect on protein structure and function, while the elasticity of these pathways offers cells the means to adapt rapidly to local changes in the environment by coordinating their protein outputs.

The Grabowski lab is currently exploring how splicing pathways exhibit elasticity, which is seen by their responsiveness to environmental stimulation and stress. We have developed the Ca2+ permeable NMDA R1 receptor as a model system to understand the biochemistry underlying the elasticity of splicing in neurons, and we are extending our experiments to other model substrates in cancer cells. We are addressing the following set of questions using genetics, biochemistry, and genomics approaches.

Which key players in signaling pathways are activated to respond to environmental cues, and how is target specificity determined?

What is the architecture of splicing codes at the level of pre-mRNA targets, and how do these codes respond to the activated pathways?
 

How are splicing pathways reset after the external stimulus fades away, and what controls the kinetics of the reset mechanisms?

 

Recent Publications
  • Dembowski JA, An P, Scoulos-Hansen M, Yeo G, Han J, Fu XD, and PJ Grabowski (2012) Alternative splicing of a novel inducible exon diversifies the CASK guanylate kinase domain. J. Nucleic Acids. 2012.2012:816237

  • Grabowski, P. (2011) Alternative splicing takes shape during development. Curr Opin Genet Dev. 21:388-94

  • Dembowski, J.A., and P.J. Grabowski (2009) The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS Genet. 5:e1000595e1000

  • Grabowski, P.J. (2007) RNA-binding proteins switch gears to drive alternative splicing in neurons. Nat. Struct. Mol. Biol. 14:577-579

  • An, P., and P.J. Grabowski (2007) Exon silencing by UAGG motifs in response to neuronal excitation. PLoS Biol. 5:e36

  • Grabowski, P.J. (2005) Splicing-active nuclear extracts from rat brain. Methods 37:323-330

  • Xu, X.M., H. Mix, B.A. Carlson, P.J. Grabowski, V.N. Gladyshev, M.J. Berry, and D.L... Hatfield (2005) Evidence for direct roles of two additional factors, SECp43 and SLA, in the selenoprotein synthesis machinery. J. Biol. Chem. 280:568-575

  • Han, K., G. Yeo, P. An, C.B. Burge, and P.J. Grabowski (2005) A combinatorial code for splicing silencing: UAGG and GGGG motifs. PLoS Biol. 3:e158

  • Grabowski, P.J. (2004) A molecular code for splicing silencing: configurations of guanosine-rich motifs. Biochem. Soc. Trans. 32:924-927

  • Miné, M., M. Brivet, G. Touati, P. Grabowski, M. Abitbol, and C. Marsac (2003) Splicing error in E1alpha pyruvate dehydrogenase mRNA caused by novel intronic mutation responsible for lactic acidosis and mental retardation. J. Biol. Chem. 278:11768-11772

  • Black, D.L., and P.J. Grabowski (2003) Alternative pre-mRNA splicing and neuronal function. Prog. Mol. Subcell. Biol. 31:187-216

  • Grabowski, P. (2002) Alternative splicing in parallel. Nat. Biotechnol. 20:346-347

  • Zhang, W., H. Liu, K. Han, and P.J. Grabowski (2002) Region specific alternative splicing in the nervous system: implications for regulation by the RNA binding protein, NAPOR. RNA 8:671-685

  • Wu, J.I., R. Reed, P.J. Grabowski, and K. Artzt (2002) The function of quaking in myelination: Regulation of alternative splicing. Proc. Natl. Acad. Sci., USA 99:4233-4238

  • Liu, H., W. Zhang, R. Reed, W. Liu, and P.J. Grabowski (2002) Mutations in RRM4 uncouple the splicing repression and RNA-binding activities of polypyrimidine tract binding protein. RNA 8:137-149

  • Grabowski, P.J., and D.L. Black (2001) Alternative RNA splicing in the nervous system. Prog. Neurobiol. 65:289-308