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Investigating the causes and consequences of replication stress in mammalian health

Final Report Summary - RSHEALTH (Investigating the causes and consequences of replication stress in mammalian health)

RSHEALTH aimed to analyze the contribution of a specific type of DNA damage that arise during DNA replication, known as Replication Stress (RS), in cancer and age-related diseases. The ultimate goal of our proposal was to use all the knowledge coming from these studies to find novel or better strategies to fight human pathologies. For instance, we developed mouse models where accelerated ageing was linked to an accumulation of RS, and later used these models to define strategies that could increase alleviate their pathologies and extend their lifespan. At the cellular level, we discovered that RS accumulates during the generation of induced pluripotent stem cells (iPSC) and contributes to the genomic instability that has been noted in this important biomedical tool. Furthermore, we also devised strategies to mitigate the accumulation of RS in iPSC and thus improve their quality. In what regards to cancer, we built up on our prior work on the development of inhibitors of the ATR kinase, the main suppressor of RS. Within RSHEALTH, our group contributed to the discovery of tumors that are particularly sensitive to these compounds, and also revealed the mechanisms of resistance to this therapy that might limit their efficacy in the clinic. Besides ATR, we helped to clarify the mechanism of action of drugs that are progressing towards the clinic such as USP7 inhibitors, and we revealed, for the first time, that tumors can arise even in the total absence of RAS oncogenes, raising an important word of caution on the potential efficacy of RAS inhibitors. While this collage is an incomplete snapshot of our activities, I think is safe to say that our work during these years has contributed to significantly advance in our understanding of RS and its impact on mammalian health.