{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T01:34:11Z","timestamp":1793324051936,"version":"4.5.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Roche Holding | Genentech","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008982","name":"QF | Qatar National Research Fund","doi-asserted-by":"publisher","award":["NPRP11S-0110-180250"],"award-info":[{"award-number":["NPRP11S-0110-180250"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,18]]},"abstract":"<jats:p>\n                    COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous\n                    <jats:italic>\n                      DET1\n                      <jats:sup>R26W<\/jats:sup>\n                    <\/jats:italic>\n                    mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1\n                    <jats:sup>R26W<\/jats:sup>\n                    impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for\n                    <jats:italic>\n                      DET1\n                      <jats:sup>R26W<\/jats:sup>\n                    <\/jats:italic>\n                    expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of\n                    <jats:italic>Det1<\/jats:italic>\n                    -deficient microglia as compared to WT microglia, indicating that the deleterious effects of the\n                    <jats:italic>DET1<\/jats:italic>\n                    p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking\n                    <jats:italic>Det1<\/jats:italic>\n                    died during embryogenesis, while\n                    <jats:italic>Det1<\/jats:italic>\n                    deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2422631122","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T13:47:01Z","timestamp":1739368021000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Impairment of DET1 causes neurological defects and lethality in mice and humans"],"prefix":"10.1073","volume":"122","author":[{"given":"Ozge","family":"Karayel","sequence":"first","affiliation":[{"name":"Department of Physiological Chemistry, Genentech","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Soung","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Genentech","place":["South San 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D.","family":"Webster","sequence":"additional","affiliation":[{"name":"Department of Pathology, Genentech","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy M.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Pathology, Genentech","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhullipala","family":"Anand","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Sidra Medicine","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naharmal","family":"Soni","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Sidra Medicine","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A.","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine","place":["Doha, Qatar"]},{"name":"Genomics, College of 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