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

M Tanori¹, A Pannicelli², E Pasquali¹

¹Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.

|January 5, 2019

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.

Insights

Homologous recombination (HR) maintains genome stability, while DNA-PKcs loss suppresses medulloblastoma (MB) by increasing DNA damage. DNA-PKcs inhibition radiosensitizes human MB cells, suggesting combined therapy potential.

Area of Science:

Molecular Biology
Genetics
Cancer Research

Background:

Double-strand breaks (DSBs) are DNA lesions that can lead to genomic instability and cancer.
Medulloblastoma (MB) is a common childhood brain tumor.
The roles of homologous recombination (HR) and non-homologous end joining (NHEJ) in DNA repair and tumorigenesis are complex.

Purpose of the Study:

To investigate the roles of HR and NHEJ in DNA damage processing and medulloblastoma (MB) development at low radiation doses.
To determine the impact of DNA-PKcs deficiency on neural precursor cells and MB tumorigenesis.
To explore the potential of combining radiotherapy with DNA-PKcs inhibition for MB treatment.

Main Methods:

Utilized Ptch1+/- mice deficient in HR or NHEJ pathways.
Exposed mice to low doses of ionizing radiation (0.042 and 0.25 Gy).
Analyzed DNA damage response (DDR) pathways, apoptosis, and tumor formation.
Investigated the effect of DNA-PKcs inhibition (NU7441) on human MB cells in vitro.

Main Results:

HR deficiency impaired genome stability, increasing spontaneous and radiation-induced oncogenic damage in cerebellar neural precursors.
Loss of DNA-PKcs function in neural precursors led to increased DSBs and apoptosis, suppressing MB tumorigenesis.
DNA-PKcs genetic inactivation resulted in radiation hypersensitivity, deregulating DDR genes and activating the p53 pathway.
Inhibition of DNA-PKcs by NU7441 radiosensitized human MB cells.

Conclusions:

HR plays a crucial role in preventing oncogenic damage in neural precursors, maintaining genome stability.
DNA-PKcs deficiency suppresses MB by enhancing DNA damage and apoptosis in tumor-initiating cells.
Targeting DNA-PKcs in combination with radiotherapy shows promise for treating medulloblastoma.

Read full analysis

Keywords:

DNA-PKcs NU7441 Rad54 Targeted therapies Tumorigenesis

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