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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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