Principal Investigator

Clara L. Kielkopf, Ph.D. University of Rochester work Box 712 601 Elmwood Ave Rochester NY 14642 p (585) 273-4799 f (585) 275-6007


Kielkopf Lab University of Rochester work MC 3-8540 601 Elmwood Ave Rochester NY 14642 p (585) 276-3681


Pre-mRNA Splicing for Treatment of Human Disease

RNA Spice Site Recognition by Key Proteins

Most human cancers, leukemia’s and many metabolic disorders are accompanied by severe defects in pre-mRNA splicing. RNA splicing is a key step of gene expression and is essential for human life. A major focus of my laboratory is to understand at a molecular level how the splicing machinery identifies sites for excision from gene transcript RNAs, which in turn changes the proteins produced. We have characterized the three-dimensional shapes of human splicing proteins recognizing one another and the gene transcript RNA [for example, Kielkopf et al. (2001); Kielkopf, Luecke, Green (2004); Sickmier et al. (2006); Jenkins et al. (2013); Wang et al. (2013)] (shown above), both at high resolution by X-ray crystallography and in solution by small-angle X-ray scattering and nuclear magnetic resonance. Through this work, we identify a network of interactions responsible for recognizing human splice sites.

Currently, our major goals investigate:

  • Determine the three-dimensional shape of the full assembly of human splicing proteins bound to the gene transcript
  • Understand the function of splicing factor phosphorylation and its potential to serve as a drug target
  • Leverage emerging views of splice site signal recognition as a basis to predictably target and correct defective splice sites

Altogether, this work would elucidate:

  • How pre-mRNA splicing fidelity is ensured in humans
  • How pre-mRNA splice site recognition is achieved in normal cells and altered in cancers and genetic disease

Current funding includes R01 GM070503 (Kielkopf): Molecular recognition during pre-mRNA splicing and F32 GM097916 (Laird): Molecular Means for 3' Splice Site Recognition by U2AF35.

Recent Publications