Eukaryotic cells need to preserve the integrity of their genomes. Conditions resulting in increased genome instability, defined as the generation and amplification of mutations and chromosomal aberrations, are associated with cancer predisposition and human pathologies. The DNA damage checkpoint acts as a surveillance mechanism that safeguards genome integrity in response to genotoxic insults. While the processes leading to DNA damage checkpoint activation have been extensively studied, little is known about mechanisms mediating its inactivation, which is essential to restore normal cell physiology and overcome genotoxic insults.A genome-wide genetic screen performed by the research group identified novel Checkpoint Inactivating Factors (CIFs). These have been implicated in inactivation via proteolysis and subcellular sorting of several substrates but were previously not been implicated in the checkpoint response. Noteworthy, human orthologs of these factors have been involved in malignant transformation and cancer development.In this project genetic, genomic, molecular biology and proteomic approaches will be used to characterize the role of these novel CIFs in the cellular response to genotoxic insults. The project also aims at identifying and characterizing CFI’s targets within the checkpoint pathway. The research proposed will contribute to elucidate how eukaryotic cells revert checkpoint activation to maintain genome integrity, thus providing a framework for the development of new therapeutic agents.CIG funding will be invested in human resource in order to boost the project’s efficacy.