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Molecular mechanisms of Wip1 phosphatase function in DNA damage response
Štorchová, Radka ; Macůrek, Libor (advisor) ; Fajkus, Jiří (referee) ; Líčeníková Hořejší, Zuzana (referee)
Human cells are constantly exposed to diverse factors causing DNA lesions, which activate the DNA damage response (DDR). Depending on the severity of DNA damage, DDR can promote temporary cell cycle arrest (checkpoint), permanent growth arrest (senescence) or programmed cell death (apoptosis). DDR signalling is regulated by a cascade of post- translational modifications, where key mediators are represented by protein kinases ATM, ATR and DNA-PK. Wip1 phosphatase (encoded by PPM1D gene) plays an important role in DDR termination by dephosphorylation of many targets of these kinases. In this thesis, we investigated checkpoint-independent functions of PPM1D in cells and described several new substrates. We discovered, that PPM1D interacts with the shelterin complex and localizes at telomeres. PPM1D dephosphorylates the shelterin component TRF2 at S410. TRF2 S410 phosphorylation enhanced TRF2 interaction with TIN2, indirectly also increasing recruitment of TPP1 to telomeres. Importantly, cells over expressing PPM1D showed increased number of telomeric fusions. These findings might be very relevant for some cancer types, in particular those expressing high levels of PPM1D or carrying C-terminally truncated mutations in PPM1D. To validate the published substrates and to detect possible new targets of...
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Regulation of the DNA damage response by R2TP mediated MRN complex assembly and control of 53BP1 localisation.
Von Morgen, Patrick ; Hořejší, Zuzana (advisor) ; Bártová, Eva (referee) ; Kleibl, Zdeněk (referee)
DNA double strand breaks are the most dangerous type of DNA damage. The MRN complex and 53BP1 have essential functions in the repair of DNA double strand breaks and are therefore important for maintaining genomic stability and preventing cancer. DNA double strand breaks are repaired by two main mechanisms - homologous recombination and non- homologous end joining. The MRN complex senses DNA double strand breaks and activates a cascade of posttranslational modifications that activates and recruits other effector proteins. In addition MRN mediated resection is important for removing adducts in non-homologous end joining and creating single stranded DNA required for homologous recombination. 53BP1 is recruited to DNA double strand breaks by site specific ubiquitinations and inhibits DNA resection, thereby promoting non-homologous end joining at the expense of homologous recombination. In this thesis we show that MRE11 binds to the R2TP chaperone complex through a CK2 mediated phosphorylation. Knockdown of R2TP or mutating the MRE11 binding site leads to decreased MRE11 levels and impaired DNA repair. Similar phenotype has been observed in cells from patients with ataxia-telangiectasia-like disorder (ATLD), containing MRE11 deletion mutation which is missing the R2TP complex binding site. Based on R2TP...
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Corruption rate and economic performance
Hořejší, Zuzana ; Soukupová, Jana (advisor) ; Džbánková, Zuzana (referee)
This Bachelor´s thesis is focused on a level of corruption and economic influence in selected countries of EU. Theoretical part is focused on a description of the term of corruption, types of corruption, forms of measuring corruption and last but not least causes and consequences of corruption. The basis of the practical part is a regression and correlation analysis which I apply to observed indicators in selected countries of EU. These observed indicators are CPI, GDP in PPP, and Legatum Prosperity Index. The aim of my thesis is to find out if there is a relation among these indicators and then how strong is a dependency among them.
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Canisterapie in Preschool Setting
HOŘEJŠÍ, Zuzana
The school leaving thesis is elaborated in order to make a connection of canistherapy with the environment of kindergartens. The thesis is devided into two main parts. The theoretical part concerns the development of an individual and the problems of canistherapy and its methods. The practical part reveals a possible connection of canistherapy effects and the environemnt of kindergartens. The aim of the practical part is to find out how the teachers are informed about this term.
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