Physiological and pharmacological relevance of DNA damage tolerance

Abstract

The DNA double helix stores the genetic information. To counteract the frequent accumulation of lesions into the DNA, cells are equipped with a complex DNA damage response network. This intricate network is capable of sensing specific DNA obstacles, and consequently activate appropriate DNA damage tolerance (DDT) and repair pathways to maintain genomic integrity. DDT has a crucial function of enabling DNA replication in presence of DNA lesions that persisted into S phase of the cell cycle or other replication roadblocks, thereby stabilizing the replication fork and prohibiting harmful secondary lesions, such as double-strand breaks. This thesis aims to unveil the overall relevance of the DDT network in genome maintenance and tissue homeostasis for mammals. A new embryonic and synthetic lethality in the DDT system is reported, which indicated the essential contribution of the DDT network for mammalian life. Of note, the earliest erythroid committed progenitor cell type was identified by performing single cell RNA-sequencing of DDT impaired hematopoietic stem and progenitor cells. In-depth ex vivo and in vitro analyses allowed to understand the molecular consequences of DDT inactivation. Furthermore, this thesis exploits the frequency of tumor specific DDT defects and proposes new therapeutic strategies in cancer. The increased cisplatin sensitivity identified in DDT defective tumors may help to predict tumor responsiveness and opens the possibility for next-generation sequencing-based personalized cancer medicine