Cellular Functions of Proteins Attending the Proteasom-ubiqitin System Lines in Relation to Tumorous Growth

Cellular Functions of Proteins Attending the Proteasom-ubiqitin System Lines in Relation to Tumorous Growth

Mgr. Klára Grantz Šašková, Ph.D.

Mgr. Klára Grantz Šašková, Ph.D. — Project head

About us

The project will focus on deciphering the function of proteasomal shuttling proteins, particulary those connected to DNA damage. For selected proteins we will prepare knock-out mice and analyze their phenotype.

Using techniques of structural biology we aim to analyze potential therapeutical targets and test small-molecule libraries for potential intervention in the process of proteasomal degradation. Furthermore, we will analyze the possibility of targeted delivery of specific nucleases to the cell nuclei for cell-specific gene therapy of tumors.

Objectives:

  • To study the celular function of both human homologues of DNA damage-inducible protein (Ddi) as well as its mouse and yeast orthologues. To identify their native substrates and interacting partners, to solve 3D structure of their individual domains and to focus on proteasomal receptors as potential therapeutic targets.
  • To develop a technique of specific gene therapy of tumors using nanostructures that specificaly target individual cells employing small-molecule ligands and harboring sequence-specific nucleases..

Our group is interested in the ubiquitin-like proteins - DNA damage-inducible protein is considered to play a role as a protein shuttle that transports certain proteins designated for degradation into the proteasome. It harbors three domains: the ubiquitin-like domain (UBL) that interacts with the proteasome, the ubiquitin-associated domain (UBA) that binds ubiquitinated substrates and, quite interestingly, the retroviral protease-like domain (RVP), which is responsible for the dimerization of the whole protein (and which originally attracted our interest due to our long-term commitment to the analysis of retroviral proteins). Although the overall fold of this domain is very similar to retropepsins including highly conserved catalytical triad (OT/SG), the putative proteolytical activity of this domain remains to be clarified. There are two human momologs of the Ddi protein. Surprisingly, their cellular role has not been revealed so far. And that is the ambitious goal of this project: we employ biochemistry, structural biology, genetics, cell biology as well as proteomics to uncover their function.

Furthermore, we have become interested in targeted delivery of various nanoparticles. Again, due to our long-term commitment in the field of virology, especially HIV virus assembly, we try to employ virus-like particles or polyplex nanoparticles as a scaffold carrying specific cargo, such as programmed nuclease for gene edditing.

Potential for cooperation

We are always looking for talented and motivated students and postdocs. 

More information about our lab is available HERE

Team

Mgr. Klára Grantz Šašková, Ph.D.

Mgr.
Klára Grantz Šašková, Ph.D.

Head of Group

saskova@email.cz
+420325873904, +420325873938
MUDr. František Sedlák

MUDr.
František Sedlák

Ph.D. student

frantisek.sedlak@natur.cuni.cz
+420325873904, +420325873938
Mgr. Monika Sivá

Mgr.
Monika Sivá

Ph.D. student

monika.siva@natur.cuni.cz
+420325873904