Cancer risk from low dose radiation in Ptch1+/- mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma.

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Cancer risk from low dose radiation in Ptch1+/- mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma.

DNA Repair (Amst). 2018 Dec 16;:

Authors: Tanori M, Pannicelli A, Pasquali E, Casciati A, Antonelli F, Giardullo P, Leonardi S, Tanno B, De Stefano I, Saran A, Mancuso M, Pazzaglia S

Abstract
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.

PMID: 30606609 [PubMed - as supplied by publisher]

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