Chronic replication stress as a source of genomic instability and inflammation
7 February 2019 - 11 h 00
Replication stress (RS) is defined as a slowing or stalling of replication forks that are caused by a variety of events of endogenous or exogenous origin. In precancerous lesions, RS is induced by the deregulation of oncogenes such as Ras, Myc or CycE. It is responsible for oncogene-induced DNA damage and associated genomic instability, a driving force of cancer development. Importantly, RS represents also the Achilles’ heel of cancer cells, which is exploited by most of the drugs used in chemotherapy to target cancer cells. Understanding the causes of spontaneous RS and characterizing the mechanisms by which cancer cells detect and respond to replication fork stalling represent therefore major challenges in cancer biology. During this lecture, I will address these three issues, with a focus on (i) transcription-replication conflicts as a source of spontaneous RS, (ii) adaptation mechanisms promoting RS tolerance in tumors and (iii) a new link between RS and inflammation that could be exploited to develop novel therapeutical strategies combining the effects of chemotherapy and immunotherapy.