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In cultured cell lines, catalytically inactive Lig4 can partially alleviate the severe DNA repair phenotypes observed in cells lacking Lig4. To study the structural role of Lig4 in vivo, a mouse strain harboring a point mutation to Lig4\u2019s catalytic site was generated. In contrast to the ablation of Lig4, catalytically inactive Lig4 mice are born alive. These mice display marked growth retardation and have clear deficits in lymphocyte development. We considered that the milder phenotype results from inactive Lig4 help to recruit another ligase to the repair complex. We next generated a mouse strain deficient for nuclear Lig3. Nuclear Lig3-deficient mice are moderately smaller and have elevated incidences of cerebral ventricle dilation but otherwise appear normal. Strikingly, in experiments crossing these two strains, mice lacking nuclear Lig3 and expressing inactive Lig4 were not obtained. Timed mating revealed that fetuses harboring both mutations underwent resorption, establishing an embryonic lethal genetic interaction. These data suggest that Lig3 is recruited to NHEJ complexes to facilitate end joining in the presence (but not activity) of Lig4.<\/jats:p>","DOI":"10.1093\/nar\/gkae1216","type":"journal-article","created":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T22:05:07Z","timestamp":1734213907000},"source":"Crossref","is-referenced-by-count":4,"title":["Lig3-dependent rescue of mouse viability and DNA double-strand break repair by catalytically inactive Lig4"],"prefix":"10.1093","volume":"53","author":[{"given":"David","family":"Medina-Su\u00e1rez","sequence":"first","affiliation":[{"name":"Department of Microbiology, Genetics and Immunology, Michigan State University , 567 Wilson Rd.,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics and Immunology, Michigan State University , 567 Wilson Rd.,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"Research Technology Support Facility, and Department of Physiology, Michigan State University , 567 Wilson Rd., East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6214-569X","authenticated-orcid":false,"given":"Jiali","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Michigan State University , 3018 Interdisciplinary Science and Technology Building,\u00a0766 Service Rd,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Michigan State University , 3018 Interdisciplinary Science and Technology Building,\u00a0766 Service 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,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9159-4489","authenticated-orcid":false,"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Michigan State University , 3018 Interdisciplinary Science and Technology Building,\u00a0766 Service Rd,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4964-331X","authenticated-orcid":false,"given":"Mauro","family":"Modesti","sequence":"additional","affiliation":[{"name":"Cancer Research Center of Marseille, Department of Genome Integrity, CNRS UMR7258, Inserm U1068, Institut Paoli-Calmettes, Aix Marseille Univ , 27 Boulevard Le\u00ef Roure CS30059,\u00a013273 Marseille Cedex 09,\u00a0Marseille ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0454-4414","authenticated-orcid":false,"given":"Katheryn","family":"Meek","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics and Immunology, Michigan State University , 567 Wilson Rd.,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]},{"name":"Department of Pathobiology & Diagnostic Investigation, Michigan State University , 567 Wilson Rd., East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie","family":"Harrington","sequence":"additional","affiliation":[{"name":"Department of Pathobiology & Diagnostic Investigation, Michigan State University , 567 Wilson Rd., East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-2812","authenticated-orcid":false,"given":"Kefei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Genetics and Immunology, Michigan State University , 567 Wilson Rd.,\u00a0East Lansing, MI\u00a048824 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,14]]},"reference":[{"key":"2025012307105156700_B1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1146\/annurev.biochem.77.061306.123941","article-title":"Eukaryotic DNA ligases: structural and functional insights","volume":"77","author":"Ellenberger","year":"2008","journal-title":"Annu. 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