Project Details
Projekt
Molecular dissection of a dynamic inositol pyrophosphate signaling pathway controlling genome stability
Subject Area
Biochemistry
Analytical Chemistry
Cell Biology
Analytical Chemistry
Cell Biology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444048842
Approximately 25 years ago, inositol phosphate derivatives carrying highly energetic diphosphate groups were discovered. These molecules were named inositol pyrophosphates (PP-InsP) and due to their rapid turnover in cells were classified as signaling molecules. The simplicity of the yeast system was instrumental for the identification of the enzymes responsible for generating PP-InsPs: IP6K and Vip1/PPIP5K comprise two classes of evolutionarily well-conserved small molecule kinase families omnipresent in eukaryotic cells. Extensive research has defined a multitude of biological pathways regulated by PP-InsPs. These range from mammalian organ development, apoptosis, insulin secretion, and weight regulation to the jasmonate-mediated wound response of plants. Pathogenic fungi infecting humans require PP-InsPs for virulence and the fungal microtubule cytoskeleton and fungal morphogenesis is PP-InsP-controlled. Interestingly, alteration of intracellular PP-InsP levels improves genome stability in yeast. Thus, controlling cellular PP-InsP pools possibly provides a means to reduce aneuploidy, which is a hallmark of cancer. While PP-InsP biology has painted an intriguing, multi-facetted picture for the relevance of PP-InsP messengers, our knowledge of the molecular mechanism of PP-InsP signaling is severely lacking behind. The key objective of this proposal is to use a model process and an easily usable model eukaryote the fission yeast Schizosaccharomyces pombe to understand the molecular basis for PP-InsP modulation. Using a combination of complimentary chemical, biochemical and genetic approaches, we will decipher how PP-InsP molecules control the chromosome-kinetochore-spindle interface and thus the fidelity of chromosome transmission. By identifying these molecular mechanisms, the proposed research has the potential to uncover unprecedented therapeutic avenues for cancer treatment in the long run.
DFG Programme
Research Grants
