Oncotarget

Research Papers:

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 and Simonetta Pazzaglia _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:100958-100974. https://doi.org/10.18632/oncotarget.10479

Metrics: PDF 1089 views  |   HTML 1649 views  |   ?  


Abstract

Mirella Tanori1, Arianna Casciati1, Francesco Berardinelli2, Simona Leonardi1, Emanuela Pasquali1, Francesca Antonelli1, Barbara Tanno1, Paola Giardullo2,3, Alessandro Pannicelli4, Gabriele Babini5, Ilaria De Stefano3, Antonella Sgura2, Mariateresa Mancuso1, Anna Saran1 and Simonetta Pazzaglia1

1 Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy

2 Department of Science, University Roma Tre, Rome, Italy

3 Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy

4 Technical Unit of Energetic Efficiency, ENEA, Rome, Italy

5 Department of Physics, University of Pavia, Pavia, Italy

Correspondence to:

Simonetta Pazzaglia, email:

Keywords: cerebellum, expression profiles, medulloblastoma, apoptosis, senescence

Received: June 14, 2016 Accepted: June 26, 2016 Published: July 07, 2016

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 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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 10479