Cellular Functions of Proteins Attending the Proteasome-Ubiquitin System Lines in Relation to Tumorous Growth

Cellular Functions of Proteins Attending the Proteasome-Ubiquitin 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.

Research Areas:

  • Ubiquitin-proteasome pathway
  • Ddi1-like proteins
  • Hepatitis B virus

Objectives:

  • Ddi1-like proteins in DNA repair and transcription regulation
  • Development of nanoparticles for mRNA targeted delivery
  • Development of antivirals targeting HBV

Content of the research:

Our junior group was established in 2016 at the research center BIOCEV. We are a proud member of the Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague.
We are interested in the family of DDI1-like proteins involved in DNA repair and transcription regulation. We also focus on hepatitis B virus and work on HBV cure.
 

In brief, we focus on Ddi1-like proteins (DNA damage-inducible protein 1) that were largely understudied, but that have been brought up to general interest in the past couple of years. The reason is simple: Ddi1-like proteins are newly discovered players involved in DNA repair and also in transcription regulation. The complete mechanism of both Ddi1 activities however still remains to be uncovered.

We are also interested in the biology of hepatitis B virus, particularly the covalently closed circular DNA (cccDNA), which resides in the nucleus of infected hepatocytes as a non-integrated plasmid-like molecule and serves as a transcriptional template for HBV. Its elimination is a key step towards possible HBV cure. We thus focus on various strategies for cccDNA degradation, such as development of nanoparticles transporting CRISPR/Cas9 system targeted to cccDNA.

Potential for cooperation

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

More information about our lab is available HERE

Publications

2019

Ramirez, J.; Lectez, B.; Osinalde, N.; Siva, M.; Elu, N.; Aloria, K.; Prochazkova, M.; Perez, C.; Martinez-Hernandez, J.; Barrio, R.; Grantz Saskova, K.; Arizmendi, JM.; Mayor, U. Quantitative proteomics reveals neuronal ubiquitination of Rngo/Ddi1 and several proteasomal subunits by Ube3a, accounting for the complexity of Angelman syndrome. Human Molecular Genetics 2019, 27 (11),1955-1971. DOI: 10.1093/hmg/ddy103

Srb, P.; Svoboda, M.; Benda, L.; Lepšík, M.; Tarábek, J.; Šícha, V.; Grüner, B.; Grantz Šašková, K.; Brynda, J.; Řezáčová, P.; Konvalinka, J.; Veverka V. Capturing a dynamically interacting inhibitor by paramagnetic NMR spectroscopy. Physical Chemistry Chemical Physics 2019, 21(10), 5661-5673. DOI: 10.1039/C9CP00416E

Svoboda, M.; Trempe, J.-F.; Konvalinka, J.; Grantz Šašková*, K. The yeast proteases Ddi1 and Wss1 are both involved in the DNA replication stress response. DNA Repair 2019, 50, 45-51, DOI: doi.org/10.1016/J.DNAREP.2019.06.008

2016

Machara, A.; Lux, V.; Kozisek, M.; Grantz Saskova, K.; Stepanek, O.; Kotora, M.; Parkan, K.; Pavova, M.; Glass, B.; Sehr, P.; Lewis, J.; Muller, B.; Krausslich, H.-G.; Konvalinka, J., Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds. J Med Chem 2016, 59 (2), 545-58. DOI: 10.1021/acs.jmedchem.5b01089

 

Siva, M.; Svoboda, M.; Veverka, V.; Trempe, J.-F.; Hofmann, K.; Kozisek, M.; Hexnerova, R.; Sedlak, F.; Belza, J.; Brynda, J.; Sacha, P.; Hubalek, M.; Starkova, J.; Flaisigova, I.; Konvalinka, J.; Grantz Saskova, K.*, Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog. Sci Rep 2016, 6, 30443. DOI: 10.1038/srep30443

Trempe, J.-F.; Saskova, K. G.; Siva, M.; Ratcliffe, C. D. H.; Veverka, V.; Hoegl, A.; Menade, M.; Feng, X.; Shenker, S.; Svoboda, M.; Kozisek, M.; Konvalinka, J.; Gehring, K., Structural studies of the yeast DNA damage-inducible protein Ddi1 reveal domain architecture of this eukaryotic protein family. Sci Rep 2016, 6, 33671. DOI: 10.1038/srep33671