{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:36:18Z","timestamp":1781109378967,"version":"3.54.1"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"19","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,5,9]]},"abstract":"<jats:p>\n                    Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the\n                    <jats:italic>XRCC4<\/jats:italic>\n                    in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4\/p53-deficient MBs have high-level\n                    <jats:italic>N-myc<\/jats:italic>\n                    gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which\n                    <jats:italic>N-myc<\/jats:italic>\n                    resides, or extrachromosomally within double minutes. In addition, most XRCC4\/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the\n                    <jats:italic>patched<\/jats:italic>\n                    gene (\n                    <jats:italic>Ptc<\/jats:italic>\n                    ), which lies on chromosome 13, was deleted in all tested XRCC4\/p53-deficient MBs in the context of translocations or interstitial deletions. In addition,\n                    <jats:italic>Cyclin D2<\/jats:italic>\n                    , a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of\n                    <jats:italic>Myc<\/jats:italic>\n                    -family or\n                    <jats:italic>Cyclin D2<\/jats:italic>\n                    genes and deletion of\n                    <jats:italic>Ptc<\/jats:italic>\n                    also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0601938103","type":"journal-article","created":{"date-parts":[[2006,5,2]],"date-time":"2006-05-02T21:30:29Z","timestamp":1146605429000},"page":"7378-7383","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":104,"title":["XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice"],"prefix":"10.1073","volume":"103","author":[{"given":"Catherine T.","family":"Yan","sequence":"first","affiliation":[{"name":"*Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research,"},{"name":"Departments of \u2020Genetics,"},{"name":"Pediatrics, 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