Resumen de Control of s-phase progression in response to stress
In response to multiple internal and external stresses, yeast cells activate a common transcriptional response known as the Environmental Stress Response (ESR), which can be problematic in S phase, when DNA is being replicated. Stress-dependent transcription can be induced unexpectedly at any moment of the cell cycle and therefore cells need a dedicated mechanism to prevent transcription-replication conflicts (TRCs) and genomic instability under these circumstances in S phase. Upon osmostress, the Hog1 SAPK is activated and phosphorylates Mrc1, a protein of the replication complex, which delays replication progression, and prevents transcription-associated recombination (TAR) and genomic instability. In this thesis, we show that the Mrc1-mediated mechanism is a general mechanism that prevents TAR and genomic instability upon heat, oxidative and low glucose stresses. In an unbiased kinome screening, we identified Mpk1, Psk1 and Snf1 as kinases able to phosphorylate the same three sites of Mrc1 and play an analogous role to Hog1 in response to heat, oxidative and low glucose stresses respectively. Finally, we also found that Mrc1 function is not restricted to environmental stress but it also plays a role upon other internal stresses that compromise cell fitness and induce the ESR response, such as the slow growth or genomic instability itself. Therefore, this thesis establishes the basis of a general mechanism, which we named “Mrc1 transcription-replication safeguard mechanism (MTR)” that protects genomic integrity from unscheduled transcriptional outbursts triggered by either environmental or internal stresses.
