|Title||Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis.|
|Publication Type||Articolo su Rivista peer-reviewed|
|Year of Publication||2016|
|Authors||Tanori, Mirella, Casciati Arianna, Berardinelli Francesco, Leonardi Simona, Pasquali Emanuela, Antonelli Francesca, Tanno Barbara, Giardullo Paola, Pannicelli Alessandro, Babini Gabriele, De Stefano Ilaria, Sgura Antonella, Mancuso Mariateresa, Saran Anna, and Pazzaglia Simonetta|
|Date Published||2016 Jul 07|
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 Rad54 and Parp-1, a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined Rad54 and Parp-1 inactivating germline mutations in Ptc1 heterozygous mice, a well-characterized model of medulloblastoma, the most common malignant pediatric brain tumor. Our study reveals that combined inactivation of Rad54 and Parp-1 causes a marked growth delay culminating in perinatallethality, providing for the first time evidence of synthetic lethal interactions between Rad54 and Parp-1 in vivo. Although the double mutation hampered investigation of Rad54 and Parp-1 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 Rad54-/-/Parp-1-/-/Ptc1+/-, and MEFs from combined Rad54/Parp-1 mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between Rad54 and Parp-1 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.
cited By 0