Cancer risk from low dose radiation in Ptch1+/- mice with inactive DNA repair systems: Therapeutic implications for medulloblastoma.
DNA Repair (Amst)
; 74: 70-79, 2019 02.
Article
en En
| MEDLINE
| ID: mdl-30606609
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Cerebelosas
/
Reparación del ADN
/
Receptor Patched-1
/
Meduloblastoma
/
Neoplasias Inducidas por Radiación
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
DNA Repair (Amst)
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Italia