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Mutations in NBS1 cause the human genomic instability syndrome Nijmegen Breakage Syndrome (NBS), of which neuronal deficits, including microcephaly and intellectual disability, are classical hallmarks. Given its function in the DDR to ensure proper proliferation and prevent death of replicating cells, NBS1 is essential for life. Here we show that, unexpectedly, Nbs1 deletion is dispensable for postmitotic neurons, but compromises their arborization and migration due to dysregulated Notch signaling. We find that Nbs1 interacts with NICD-RBPJ, the effector of Notch signaling, and inhibits Notch activity. Genetic ablation or pharmaceutical inhibition of Notch signaling rescues the maturation and migration defects of Nbs1-deficient neurons in vitro and in vivo. Upregulation of Notch by Nbs1 deletion is independent of the key DDR downstream effector p53 and inactivation of each MRN component produces a different pattern of Notch activity and distinct neuronal defects. These data indicate that neuronal defects and aberrant Notch activity in Nbs1-deficient cells are unlikely to be a direct consequence of loss of MRN-mediated DDR function. This study discloses a novel function of NBS1 in crosstalk with the Notch pathway in neuron development.<\/jats:p>","DOI":"10.1093\/nar\/gkaa716","type":"journal-article","created":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T11:10:31Z","timestamp":1598267431000},"page":"10924-10939","source":"Crossref","is-referenced-by-count":20,"title":["NBS1 interacts with Notch signaling in neuronal homeostasis"],"prefix":"10.1093","volume":"48","author":[{"given":"Zhong-Wei","family":"Zhou","sequence":"first","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"},{"name":"School of Medicine (Shenzhen), Sun Yat-Sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Kirtay","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Schneble","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Yakoub","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingmei","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Medicine (Shenzhen), Sun Yat-Sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"R\u00fcdiger","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanstantsin","family":"Siniuk","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqing","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Medicine (Shenzhen), Sun Yat-Sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Nan","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Medicine (Shenzhen), Sun Yat-Sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0671-9166","authenticated-orcid":false,"given":"Tang-Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"},{"name":"Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kaether","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Barzilai","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-3485","authenticated-orcid":false,"given":"Zhao-Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging \u2013 Fritz Lipmann Institute (FLI), Jena, Germany"},{"name":"Faculty of Biological Sciences, Friedrich-Schiller-University Jena, Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,10,3]]},"reference":[{"key":"2020110419235277700_B1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nrm3047","article-title":"The MRE11 complex: starting from the ends","volume":"12","author":"Stracker","year":"2011","journal-title":"Nat. Rev. Mol. 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