DNA ligase IV suppresses medulloblastoma formation.
Substantial neural defects are often present in mice with targeted inactivation of DNA repair factors such as DNA ligase IV (Lig4). Whereas Lig4(-/-) mice undergo widespread neural apoptosis and die during development, p53 deficiency rescues this death. We found that all Lig4(-/-)p53(-/-) mice developed medulloblastoma, but did not develop other tumors of the nervous system. Lig4(-/-)p53(-/-) medulloblastoma occurred as early as 21 days of age, originated in the external granule layer of the developing cerebellum, and was synaptophysin immunoreactive. These data reveal a pronounced susceptibility of the cerebellum to the effects of chronic DNA damage and provide a direct link between genotoxic stress and medulloblastoma formation.
Lee
Youngsoo
Y
Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
McKinnon
Peter J
PJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002528:Cerebellar Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008527:Medulloblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D000072481:DNA Ligase ATP; D011088:DNA Ligases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C500943:Atoh1 protein, mouse