In this renewal, Dr. Durocher and his team proposes to build on their discovery of a cellular communication system, underpinned by the RNF8 and RNF168 proteins, that employ the small protein ubiquitin. This cellular signaling pathway orchestrates the assembly of DNA repair complexes at the site of chromosome breaks to promote their repair. Since chromosome breaks and their aberrant repair are necessary intermediates of most cancers, this work will help elucidate how normal cells normally mitigate the adverse impact of chromosome breaks and how this process goes awry during tumorigenesis. This work might reveal new strategies to target cancer but in the shorter term, this work will result an understanding of how the RNF8 and RNF168 proteins participate in maintaining the integrity of our genome.