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Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum.

TitoloOpposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum.
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2011
AutoriTanori, Mirella, Pasquali Emanuela, Leonardi Simona, Giardullo Paola, Di Majo V, Taccioli G, Essers J, Kanaar R, Mullenders L H., Atkinson M J., Mancuso Mariateresa, Saran Anna, and Pazzaglia Simonetta
RivistaOncogene
Volume30
Issue47
Paginazione4740-9
Data di pubblicazione2011 Nov 24
ISSN14765594
Parole chiaveAnimals, Cerebellar Neoplasms, DNA damage, DNA End-Joining Repair, DNA Helicases, DNA-Activated Protein Kinase, genomic instability, homologous recombination, Loss of Heterozygosity, medulloblastoma, Mice, Nuclear Proteins, patched receptors, Patched-1 Receptor, Receptors, Cell Surface, risk
Abstract

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.

DOI10.1038/onc.2011.178
Alternate JournalOncogene
Citation Key5066
PubMed ID21602895