{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:16:07Z","timestamp":1792840567110,"version":"4.5.0"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA100504"],"award-info":[{"award-number":["CA100504"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM118009"],"award-info":[{"award-number":["GM118009"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for double-strand DNA breaks. Artemis activation by DNA-PKcs resolves hairpin DNA ends formed during V(D)J recombination. Artemis deficiency disrupts development of adaptive immunity and leads to radiosensitive T- B- severe combined immunodeficiency (RS-SCID). An activated state of Artemis in complex with DNA-PK was solved by cryo-EM recently, which showed Artemis bound to the DNA. Here, we report that the pre-activated form (basal state) of the Artemis:DNA-PKcs complex is stable on an agarose-acrylamide gel system, and suitable for cryo-EM structural analysis. Structures show that the Artemis catalytic domain is dynamically positioned externally to DNA-PKcs prior to ABCDE autophosphorylation and show how both the catalytic and regulatory domains of Artemis interact with the N-HEAT and FAT domains of DNA-PKcs. We define a mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs and show that an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. All of the findings are useful in explaining how a hypomorphic L3062R missense mutation of DNA-PKcs could lead to insufficient Artemis activation, hence RS-SCID. Our results provide various target site candidates to design disruptors for Artemis:DNA-PKcs complex formation.<\/jats:p>","DOI":"10.1093\/nar\/gkac564","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T09:12:09Z","timestamp":1657271529000},"page":"7697-7720","source":"Crossref","is-referenced-by-count":35,"title":["Structural analysis of the basal state of the Artemis:DNA-PKcs complex"],"prefix":"10.1093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3911-3021","authenticated-orcid":false,"given":"Go","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Pathology, Department of Biochemistry & Molecular Biology, Department of Molecular Microbiology & Immunology, and Section of Computational & Molecular Biology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine , 1441 Eastlake Ave, Rm. 5428, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3700-6345","authenticated-orcid":false,"given":"Michael R","family":"Lieber","sequence":"additional","affiliation":[{"name":"Department of Pathology, Department of Biochemistry & Molecular Biology, Department of Molecular Microbiology & Immunology, and Section of Computational & Molecular Biology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine , 1441 Eastlake Ave, Rm. 5428, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8942-8131","authenticated-orcid":false,"given":"Dewight R","family":"Williams","sequence":"additional","affiliation":[{"name":"Eyring Materials Center, John Cowley Center for High Resolution Electron Microscopy, Arizona State University , Tempe, AZ 85281, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"2022072200011688000_B1","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41580-020-00297-8","article-title":"The molecular basis and disease relevance of non-homologous DNA end joining","volume":"21","author":"Zhao","year":"2020","journal-title":"Nat. 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