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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 homolog...

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Autores principales: 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, Pazzaglia, Simonetta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731848/
https://www.ncbi.nlm.nih.gov/pubmed/29254138
http://dx.doi.org/10.18632/oncotarget.10479
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author 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
Pazzaglia, Simonetta
author_facet 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
Pazzaglia, Simonetta
author_sort Tanori, Mirella
collection PubMed
description 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.
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spelling pubmed-57318482017-12-17 Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis 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 Pazzaglia, Simonetta Oncotarget Research Paper 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. Impact Journals LLC 2016-07-07 /pmc/articles/PMC5731848/ /pubmed/29254138 http://dx.doi.org/10.18632/oncotarget.10479 Text en Copyright: © 2017 Tanori et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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
Pazzaglia, Simonetta
Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title_full Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title_fullStr Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title_full_unstemmed Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title_short Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis
title_sort synthetic lethal genetic interactions between rad54 and parp-1 in mouse development and oncogenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731848/
https://www.ncbi.nlm.nih.gov/pubmed/29254138
http://dx.doi.org/10.18632/oncotarget.10479
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