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Defects in DNA repair and RNA metabolism associated with human neurological disorders
Cihlářová, Zuzana ; Hanzlíková, Hana (advisor) ; Čermák, Lukáš (referee) ; Roithová, Adriana (referee)
The human genome is constantly under the attack by various damaging agents, leading to the breakage of one or both strands of DNA that might interfere with RNA processing. Importantly, our cells have evolved diverse mechanisms to rapidly repair various DNA lesions, highlighting the importance of genetic integrity. Defects in DNA repair and/or RNA metabolism can lead to a variety of human hereditary diseases, with pathologies including growth and developmental defects, immunodeficiency, predisposition to cancer, and neurodegeneration. Mutations in the BRAT1 (BRCA1-associated ATM activator-1) protein have been associated with neurological disorders characterized by heterogenous phenotypes with varying levels of clinical severity ranging from microcephaly, hypertonia, epilepsy, seizures, and early death in the first two years of life to mild cerebellar atrophy and ataxia. Previously, BRAT1 protein has been implicated in the cellular response to DNA double-strand breaks and ATM signalling. However, the exact mechanism/s by which mutations in BRAT1 gene trigger neurological disorders are largely unknown. Recently, we have identified a homozygous missense c.185T>A (p.Val62Glu) variant in BRAT1 that markedly reduced the level of BRAT1 protein in patient-derived cell lines. Surprisingly, our data show that...
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Exosome and its role in RNA metabolism of budding yeast S. cerevisiae
Holická, Eliška ; Půta, František (advisor) ; Groušl, Tomáš (referee)
Exosome is a protein complex present in the yeast nucleus and cytoplasm, which participates in RNA degradation, processing and turnover. The core of exosome consists of nine catalytically inactive subunits, which physically associate with RNA nuclease Rrp44. The function of exosome is dependent on many cofactors or facultatively associated enzymes, and these associations provide high versatility of the complex. In different compartments the complex works by other means and plays a role in distinct processes. In nucleus, exosome acts mainly in pre-RNA processing, whereas in cytoplasm its major role is to degrade native mRNA. Nevertheless, in all of these processes, its general role is the 3' exonucleolytic cleavage of single-stranded RNA. Exosome has homologs in many various kinds of organisms - e. g. different types of bacterial nucleases, archeal exosome, human PM-Scl complex (or exosome), which implicates high conservation of this degradation machinery. Thus, it is very likely that some exosome components lost their original function over the evolution, more than that the yeast exosome is an evolutionary innovation.
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