|Title||Cancer risk from low dose radiation in Ptch1+ / − mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma|
|Publication Type||Articolo su Rivista peer-reviewed|
|Year of Publication||2019|
|Authors||Tanori, Mirella, Pannicelli A., Pasquali Emanuela, Casciati Arianna, Antonelli Francesca, Giardullo Paola, Leonardi Simona, Tanno Barbara, De Stefano Ilaria, Saran Anna, Mancuso Mariateresa, and Pazzaglia Simonetta|
|Keywords||animal tissue, Apoptosis, article, cancer risk, cancer stem cell, carcinogenesis, cell cycle arrest, cerebellum, DNA damage, DNA damage response, DNA end joining repair, DNA repair, genomic instability, human, human cell, low energy radiation, medulloblastoma, mouse, nonhuman, priority journal, protein p53, protein Patched 1, radiation dose|
DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/− mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/− mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation. © 2018 Elsevier B.V.
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