About 10 years ago, breakthrough studies established oncogene-induced replication stress as an early, driving event in tumourigenesis. Deregulated DNA replication fuels genomic instability, driving precancerous lesions into full cellular transformation by inactivation of key DNA damage checkpoint genes. These findings have significantly shifted the research interests in the genome stability field, thus far mainly DSB repair-oriented, towards the mechanisms controlling DNA replication stress. At the same time, the high proliferative surge of cancer cells represents the main biological target of current chemotherapeutic strategy. Moreover, specific genetic defects in mechanisms controlling genome integrity maintenance have been recently exploited to identify druggable targets aimed at selectively killing cancer cells carrying well-defined genetic inactivation. Homologous Recombination (HR) factors, such as BRCA1 and BRCA2, represent a paradigmatic example of tumour suppressor genes, linking genome instability and cancer susceptibility; somatic and acquired mutations in this genes are responsible for approximately 30% of breast and ovarian tumors and the cumulative risk for developing cancer ranged from 49% to 57% in women with BRCA1 or BRCA2 mutations by the age of 70 years. At the same time, genetic defects in these genes confer exquisite sensitivity to clinically relevant chemotherapeutic agents, such as Cisplatin and PARP inhibitors. Nevertheless, the clinical efficacy of these treatments has been limited by the high occurrence of chemoresistence cases.
Besides the well-established role of HR factors in classical double-strand breaks (DSB) repair, a growing body of literature has recently pointed towards a more penetrant, clinically-relevant role in managing DNA replication stress. By using an integrated, multidisciplinary experimental strategy, combining microscopy-based high-throughput screenings with single-molecule and biochemical approaches, this project has been conceived to mechanistically dissect the role of HR during replication stress, besides its well-characterised function in DSB repair, and to identify new HR factors specifically involved in this process.
This project has significantly helped to define the molecular basis of cancers harbouring HR-defective genetic background, but it also provides the groundwork for the identification of new targets to be exploited to selectively kill cancer cells or to overcome their acquired resistance to common chemotherapeutic strategies.
