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

Mirella Tanori, Arianna Casciati, Francesco Berardinelli, Simona Leonardi, Emanuela Pasquali, Francesca Antonelli, Barbara Tanno, Paola Giardullo, Alessandro Pannicelli, Gabriele Babini, Ilaria De Stefano, Antonella Sgura, Mariateresa Mancuso, Anna Saran, Simonetta Pazzaglia

Research output: Contribution to journalArticle

Abstract

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 perinatal lethality, 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 networkbased 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.
Original languageEnglish
Pages (from-to)100958 - 100974
Number of pages17
JournalOncotarget
Volume8
Issue number60
DOIs
Publication statusPublished - 2017
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Oncology

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