Mirka Uhlirova - A 12

Cutting through the tumor complexity: Role of splicing in epithelial homeostasis and tumorigenesis

Abstract

Pre-mRNA splicing is a critical step in the regulation of gene expression, contributing to a significant expansion of proteome diversity and functional complexity in metazoans. Selective intron removal is catalyzed by a dynamic ribonucleoprotein machine called the spliceosome. Strikingly, spliceosome components are frequently mutated and deregulated in multiple cancer types, and mounting evidence implicates splicing factors as gatekeepers of genome stability. The overall goal of this project is to decipher how spliceosome dysfunction, caused by malfunction of the evolutionarily conserved splicing regulators contributes to the breakdown of epithelial homeostasis and tumorigenesis. By combining Omic technologies with forward and reverse genetics in Drosophila and mouse model, we aim to identify the genetic network that links aberrant splicing to genome instability, to determine the mechanisms that underlie differential cell and transcript sensitivity to splicing factor deficiency and to study how spliceosome dysfunction impacts skin homeostasis and drives tumorigenesis in mammals.

Clinical/medical relevance and sustainability in disease understanding

Splicing factors are frequently altered in various human cancers. Thus, drugging the spliceosome appears to be a viable therapeutic option. Indeed, several compounds have shown marked anti-tumor effects and entered clinical trials. A deeper understanding of the normal role of individual splicing regulators and their functional impact when deregulated are crucial for the development of new splicing modulators and inhibitors that can be used as effective next generation anti-cancer drugs.


Prof. Dr. rer. nat. Mirka Uhlirova

Institute for Genetics, CECAD Cologne

Prof. Dr. rer. nat. Mirka Uhlirova

Principal Investigator A 12

Mirka.Uhlirova@uni-koeln.de

Work +49 221 478 84334

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

Publications - Mirka Uhlirova

Link to PubMed