Final Report Summary - DDREGULATION (Regulation of DNA damage responses at the replication fork) Complete and accurate replication of cellular DNA during each cell cycle is vital for the transmission of genetic information and for cell and organismal survival. However, the integrity of DNA is continuously challenged by numerous genotoxic insults that threaten the fidelity of the DNA replication process and may lead to irreversible and unwanted changes to the genetic material. Accordingly, all cells are equipped with a sophisticated DNA damage response that enables efficient sensing and resolution of a broad range of DNA lesions and other genotoxic insults, thereby forming a crucial protective barrier to genomic instability. This ERC Consolidator project aimed to comprehensively explore and characterize the cellular proteins and signaling processes operating directly at the DNA replication machinery upon DNA damage and other genotoxic stresses to mitigate the adverse impact of these insults. The project fostered the development and application of novel, groundbreaking methodology for systems-wide identification of the proteins functioning directly in the context of sites of DNA damage and replication stress, allowing for comprehensive illumination of the architecture and dynamics of entire genome stability maintenance processes. Building on this technology, the project discovered and functionally characterized an extensive range of new genome stability maintenance factors and provided important novel mechanistic insights into how protein signaling mediated by ubiquitin and ubiquitin-like modifiers function to prevent deleterious genetic changes in response to different types of DNA damage and replication stress. Collectively, the outcomes of the project have made important contributions to improving our insights into the orchestration, regulation and complexity of protective intracellular responses to genotoxic insults that are instrumental for the maintenance of cell and organismal fitness.