Mechanické poznatky o replikačním stresu indukovaném onkogeny a jeho řešení

Huňová Oravetzová, Anna

DNA replication is a fundamental process in which the faithful duplication of the genome is essential for cell viability. However, this process is frequently threatened by replication stress, which is defined as the slowing or stalling of ongoing replication forks. This phenomenon is a major source of genome instability and a hallmark of cancer development. In recent years, research has identified R-loops (co-transcriptionally formed RNA:DNA hybrid structures containing a single-stranded DNA loop) and transcription-replication collisions (TRCs) as key drivers of replication stress. If left unresolved, these obstacles can severely impair genome integrity during mitosis, leading to chromosomal instability. In this work, we provide new mechanistic insights into the MUS81-ELL-LIG4 replication restart pathway that operates at sites of R-loop-mediated TRCs to maintain genome stability. Specifically, we identify DDX17 as the helicase responsible for R-loop removal and demonstrate that the primase/polymerase PRIMPOL facilitates replication restart. Furthermore, our work advances the understanding of the causes of R-loop-mediated replication stress. We show that elevated levels of reactive oxygen species (ROS) induce R-loop formation at sites of TRCs in a manner dependent on the replisome-associated ROS...

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