Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis.

Mutations in DNA repair pathways are frequent in human cancers. Hence, gaining insights into the interaction of DNA repair genes is key to development of novel tumor-specific treatment strategies. In this study, we tested the functional relationship in development and oncogenesis between the homologous recombination (HR) factor and , a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined and inactivating germline mutations in heterozygous mice, a well-characterized model of medulloblastoma, the most common malignant pediatric brain tumor. Our study reveals that combined inactivation of and causes a marked growth delay culminating in perinatallethality, providing for the first time evidence of synthetic lethal interactions between and . Although the double mutation hampered investigation of and interactions in cerebellum tumorigenesis, insights were gained by showing accumulation of endogenous DNA damage and increased apoptotic rate in granule cell precursors (GCPs). A network-based approach to detect differential expression of DNA repair genes in the cerebellum revealed perturbation of p53 signaling in //, and MEFs from combined mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between and by suggesting that p53/p21-mediated apoptosis and/or senescence may be involved in synthetic lethal interactions occurring during development and inhibition of tumor growth.