{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:10:17Z","timestamp":1790759417267,"version":"4.1.0"},"reference-count":76,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T00:00:00Z","timestamp":1688860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FR2704\/3\u20131"],"award-info":[{"award-number":["FR2704\/3\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pericles.pericles-gcp.literatumonline.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11\u2010RAD50\u2010NBS1 (MRN) complex that binds to DNA double\u2010strand breaks and activates the DNA damage response (DDR). <jats:italic>Nbs1<\/jats:italic> inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, <jats:italic>p53<\/jats:italic> homozygous deletion rescues the NBS1\u2010deficient phenotype allowing long\u2010term survival. The objective of this work was to determine whether simultaneous inactivation of <jats:italic>Nbs1<\/jats:italic> and <jats:italic>p53<\/jats:italic> in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated a mouse model with simultaneous genetic inactivation of <jats:italic>Nbs1<\/jats:italic> and <jats:italic>p53<\/jats:italic> in embryonic neural stem cells and analysed the arising tumours with in\u2010depth molecular analyses including immunohistochemistry, array comparative genomic hybridisation (aCGH), whole exome\u2010sequencing and RNA\u2010sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NBS1\/P53\u2010deficient mice develop high\u2010grade gliomas (HGG) arising in the olfactory bulbs and in the cortex along the rostral migratory stream. In\u2010depth molecular analyses using immunohistochemistry, aCGH, whole exome\u2010sequencing and RNA\u2010sequencing revealed striking similarities to paediatric human HGG with shared features with radiation\u2010induced gliomas (RIGs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings show that concomitant inactivation of <jats:italic>Nbs1<\/jats:italic> and <jats:italic>p53<\/jats:italic> in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12915","type":"journal-article","created":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T03:43:58Z","timestamp":1686368638000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Simultaneous <i>Nbs1<\/i> and <i>p53<\/i> inactivation in neural progenitors triggers high\u2010grade gliomas"],"prefix":"10.1111","volume":"49","author":[{"given":"David E.","family":"Reuss","sequence":"first","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"Consortium for Translational Cancer Research (DKTK)  Heidelberg Germany"},{"name":"Department of Neuropathology, Institute of Pathology Ruprecht\u2010Karls\u2010Universit\u00e4t Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna M.","family":"Downing","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristel V.","family":"Camacho","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario M.","family":"Piro","sequence":"additional","affiliation":[{"name":"Dipartimento di Elettronica, Informazione e Bioingegneria (DEIB) Politecnico di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Herold\u2010Mende","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Ruprecht\u2010Karls\u2010Universit\u00e4t Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao\u2010Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Ageing\u2010Fritz Lipmann Institute  Jena Germany"},{"name":"State Key Laboratory of Microbial Technology Shandong University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-1962","authenticated-orcid":false,"given":"Felix","family":"Sahm","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"Consortium for Translational Cancer Research (DKTK)  Heidelberg Germany"},{"name":"Department of Neuropathology, Institute of Pathology Ruprecht\u2010Karls\u2010Universit\u00e4t Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"von Deimling","sequence":"additional","affiliation":[{"name":"Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"Consortium for Translational Cancer Research (DKTK)  Heidelberg Germany"},{"name":"Department of Neuropathology, Institute of Pathology Ruprecht\u2010Karls\u2010Universit\u00e4t Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"McKinnon","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research, St. Jude Translational Neuroscience, Departments of Genetics and Cell and Molecular Biology St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre\u2010Olivier","family":"Frappart","sequence":"additional","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/25292"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1385\/NMM:8:4:495"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20107\u201013"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2004.02.022"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399\u20100004.2002.620112.x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19961002)65:1<21::AID-AJMG3>3.0.CO;2-0"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/mpo.10275"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.486"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201003\u20102502"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469\u20101809.2002.00122.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22280"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20239"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23168"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549\u2010007\u20109820\u20104"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11231"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.01.006"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008390\u2010200308000\u201000005"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30116"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.04.056"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.06.026"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960\u20109822(01)00019\u20107"},{"issue":"21","key":"e_1_2_11_23_1","first-page":"7263","article-title":"Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation\u2010induced tumorigenesis","volume":"63","author":"Dumon\u2010Jones V","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.6.1447"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1228"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806882106"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601938103"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601703"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069209"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010013\u20101093\u2010x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010015\u20101519\u20108"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010019\u201002039\u20103"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.12.020"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4178\u201007.2008"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.034"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07385"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11284"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16478"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22973"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11329"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11213"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201019\u20100909"},{"issue":"509","key":"e_1_2_11_46_1","article-title":"Proteogenomic and metabolomic characterization of human glioblastoma","volume":"39","author":"Wang LB","year":"2021","journal-title":"Cancer Cell"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010019\u20100349\u2010y"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8470"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2011.1421"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31819724c2"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414389111"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2012.3"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010physiol\u2010030212\u2010183653"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12837"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010009\u20100608\u2010y"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20100\u2010387\u201072005\u20100_6"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1097\/00043426\u2010200303000\u201000013"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960\u20109822(02)00763\u20107"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1270"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750\u20103639.2008.00234.x"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.01.039"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25709"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2938"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/215135"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201019\u20101030"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025709\u2010x"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025708\u2010y"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010018\u20101906\u2010z"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10143\u2010016\u20100786\u20108"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.29"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201019\u20100680"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535\u20106108(02)00017\u2010X"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.52"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.04.012"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201012271\u2010w"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201033535\u2010y"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rrw034"}],"container-title":["Neuropathology and Applied Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nan.12915","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T11:59:58Z","timestamp":1693915198000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/nan.12915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,9]]},"references-count":76,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1111\/nan.12915"],"URL":"https:\/\/doi.org\/10.1111\/nan.12915","archive":["Portico"],"relation":{},"ISSN":["0305-1846","1365-2990"],"issn-type":[{"value":"0305-1846","type":"print"},{"value":"1365-2990","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,9]]},"assertion":[{"value":"2022-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12915"}}