Principal Investigator

Photo of Clara Kielkopf
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

Contact

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

Affiliations

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); Gupta, Jenkins, Kielkopf (2011)] (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:

  • The three-dimensional shapes of the full assembly of human proteins bound to the gene transcript
  • The interactions among Aspergillus fumigatus splicing factors, a soil fungus that frequently causes pulmonary infections in AIDS patients.
  • Function and potential of splicing factor phosphorylation to serve as a drug target

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
  • Differences between Aspergillus and human splicing factors for targeting by small molecule therapeutics

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.