| First Author | Tanori M | Year | 2019 |
| Journal | DNA Repair (Amst) | Volume | 74 |
| Pages | 70-79 | PubMed ID | 30606609 |
| Mgi Jnum | J:294551 | Mgi Id | MGI:6454141 |
| Doi | 10.1016/j.dnarep.2018.12.003 | Citation | Tanori M, et al. (2019) Cancer risk from low dose radiation in Ptch1(+)(/)(-) mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma. DNA Repair (Amst) 74:70-79 |
| abstractText | 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. |
