Exploring transcription-mediated replication stress and RNA-DNA hybrids as targets of anticancer drugs

Resumen del trabajo presentado al 15th International Congress Targeting Anticancer Therapies (TAT), celebrado en Paris (Francia) del 6 al 8 de marzo de 2017.Replication stress is likely the most important source of genome instability and a hallmark of cancer cells. There is large amount of evidence that most cancer cells suffer replication stress as a consequence of either failure in replication or the DNA damage response (DDR) or of cell cycle and metabolic changes. Transcription may be a major endogenous source of replication stress and genome instability. Collisions between the transcription and replication can result in DNA breaks that need to be repaired to avoid replication stress, genome rearrangements and cell proliferation defects. An element enhancing and likely being the major responsible of transcription-replication collisions is the formation of RNA-DNA hybrids. Therefore, given the association of R loops with replication stress and genome instability and that these are hallmarks of cancer, we are investigating whether the action of specific anticancer drugs may be via an effect on R loop accumulation or R loop-dependent replication stress. With this aim we have investigated the action of a specific anticancer drug on different human cell lines which either normal or increased levels of R loops. Analysis of DNA breakage accumulation, cell proliferation, replication fork progression or R loop accumulation in response to treatment with different doses has permitted us to evaluate the implication of R loops in the mechanism of action of this anticancer drug, and up to which point R loops and/or transcription replication collisions can be taken into account as putative targets of some anticancer drugs.Peer Reviewe