DNA double-strand breaks (DSBs) can arise through exposure to exogenous DNA damaging agents such as ionizing radiation, as well as through endogenous means; for example, via DNA replication fork collapse. Irrespective of the source, the physical severing of the sugar-phosphate backbone represents an acute threat to organismal viability and genome stability. Hanahan and Weinberg describe genome instability and mutation as an enabling characteristic of cancer. 1 Indeed, chromosome structural rearrangements, which are pervasive in cancer, invariably arise from DSB repair gone awry. To deal with this threat, all cells have evolved 2 principal means to repair DSBs: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is predominantly a conservative and error-free process, employing a homologous template, usually the sister chromatid, to repair the break. RAD51, the eukaryotic ortholog of bacterial RecA, is the major HR protein. Conversely, NHEJ is typically error-prone, and rejoins the break without regard for the state of the ends, often resulting in loss of nucleotides or the re-joining of noncontiguous ends. Exemplifying the importance of HR, many key tumor suppressor genes encode central HR players, eg BRCA1 and BRCA2. Furthermore, several genetic diseases characterized by increased cancer risk are caused by mutations in HR genes, one example of which is Fanconi anemia (FA). FA is clinically characterized by congenital defects, bone marrow failure, and increased cancer risk. 2 FA is caused by mutation of any one of 20 known genes, which encode proteins that function cooperatively in the FA-BRCA pathway to promote HR. 3 The molecular links between FA and HR are an area of active investigation. Evidence presented in this volume of Cell Cycle points to a novel noncanonical connection between enzymes involved in the major regulatory step of the FA-BRCA pathway and a key HR effector. 4 This regulatory step is the site-specific monoubiquitination of the FANCD2 and FANCI proteins. The E2 ubiquitin-conjugating enzyme FANCT/UBE2T and the E3 ubiquitin ligase FANCL catalyze the forward step of this reaction. The reverse stepdeubiquitination-is catalyzed by the USP1 deubiquitinating enzyme (DUB) and its heterodimeric binding partner