Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum
Heterozygous Patched1 (Ptc1-/-) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1-/-mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1-/-mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.
|Keywords||DNA-PKcs, LOH, Medulloblastoma, Rad54, Radiation|
|Persistent URL||dx.doi.org/10.1038/onc.2011.178, hdl.handle.net/1765/33998|
|Journal||Oncogene: including Oncogene Reviews|
Tanori, M, Pasquali, E, Leonardi, S, Giardullo, P, di Majo, V, Taccioli, G, … Pazzaglia, S. (2011). Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum. Oncogene: including Oncogene Reviews, 30(47), 4740–4749. doi:10.1038/onc.2011.178