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Molecular mechanisms of genome integrity maintenance under conditions of replication stress
Boleslavská, Barbora ; Dobrovolná, Jana (advisor) ; Hanzlíková, Hana (referee) ; Šebesta, Marek (referee)
Precise and timely duplication of chromosomal DNA is an essential process for all dividing cells. Failure to complete this process can lead to cell death or irreversible changes in genetic information ultimately leading to cell transformation and cancer. The sophisticated multiprotein complex ensuring DNA replication is often slowed down or stalled by numerous obstacles, including DNA lesions and secondary DNA structures, but also by another vitally important cellular process - by ongoing DNA transcription. Head-on transcription-replication collisions (TRCs) associated with the formation of R-loop structures are the major endogenous source of genomic instability. R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid and displaced DNA strand, with a strong potential to halt replication fork progression and to have a genotoxic effect. To ensure complete DNA replication, the eukaryotic cells have developed various mechanisms for removal and overcoming the obstacles to replication fork progression. However, despite the extensive research, the molecular mechanisms underlying the restart of R-loop-stalled replication forks remain unclear. Here, we provide evidence that in human cells the restart of DNA synthesis at the sites of TRCs is a multi-step process involving fork...
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Genomic instability associated with formation of RNA:DNA hybrids and molecular mechanisms of its suppression
Naščáková, Zuzana ; Dobrovolná, Jana (advisor) ; Hanzlíková, Hana (referee) ; Šolc, Petr (referee)
One of the most common infections of a human organism is an infection of stomach induced by pathogenic bacteria Helicobacter pylori (H. pylori). It is estimated that every second person is infected, with even higher prevalence in developing countries. As a quiet enemy, H. pylori can colonise a human stomach for decades without manifestation of infection-associated symptoms. However, chronic infection may cause severe damage to the stomach tissue, subsequently leading to the development of gastric diseases, including gastritis and ulcer disease. H. pylori infection is also a driving cause of gastric cancer, with 80% of gastric cancers being associated with chronic infection. H. pylori ensures its life-long persistence in a human host organism via the action of its virulence factors, which have a pleiotropic effect on multiple systems, mostly acting on the attenuation of a human immune system and the induction of atrophy of stomach tissue. The irreversible changes of stomach epithelium are induced by activation of an innate immune response in H. pylori-exposed epithelial cells through the stimulation of ALPK1/TIFA/NF-κB signalling pathway upon a recognition of β-ADP heptose, an intermediate product of bacterial lipopolysaccharide biosynthesis, and consequently leading to the formation of DNA...
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Genomic instability associated with formation of RNA:DNA hybrids and molecular mechanisms of its suppression
Naščáková, Zuzana ; Dobrovolná, Jana (advisor) ; Hanzlíková, Hana (referee) ; Šolc, Petr (referee)
One of the most common infections of a human organism is an infection of stomach induced by pathogenic bacteria Helicobacter pylori (H. pylori). It is estimated that every second person is infected, with even higher prevalence in developing countries. As a quiet enemy, H. pylori can colonise a human stomach for decades without manifestation of infection-associated symptoms. However, chronic infection may cause severe damage to the stomach tissue, subsequently leading to the development of gastric diseases, including gastritis and ulcer disease. H. pylori infection is also a driving cause of gastric cancer, with 80% of gastric cancers being associated with chronic infection. H. pylori ensures its life-long persistence in a human host organism via the action of its virulence factors, which have a pleiotropic effect on multiple systems, mostly acting on the attenuation of a human immune system and the induction of atrophy of stomach tissue. The irreversible changes of stomach epithelium are induced by activation of an innate immune response in H. pylori-exposed epithelial cells through the stimulation of ALPK1/TIFA/NF-κB signalling pathway upon a recognition of β-ADP heptose, an intermediate product of bacterial lipopolysaccharide biosynthesis, and consequently leading to the formation of DNA...
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