{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:51:19Z","timestamp":1790805079878,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T00:00:00Z","timestamp":1574899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["249774"],"award-info":[{"award-number":["249774"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["270491"],"award-info":[{"award-number":["270491"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["291217"],"award-info":[{"award-number":["291217"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004590","name":"Helse Midt-Norge","doi-asserted-by":"publisher","award":["13477"],"award-info":[{"award-number":["13477"]}],"id":[{"id":"10.13039\/501100004590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","award":["182355"],"award-info":[{"award-number":["182355"]}],"id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NTNU Outstanding Academic Fellow 2017-2021","award":["1"],"award-info":[{"award-number":["1"]}]},{"DOI":"10.13039\/501100010790","name":"Erasmus+","doi-asserted-by":"publisher","award":["JW"],"award-info":[{"award-number":["JW"]}],"id":[{"id":"10.13039\/501100010790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. Mutations in several NHEJ genes result in neurological abnormalities and immunodeficiency both in humans and mice. The NHEJ pathway is required for V(D)J recombination in developing B and T lymphocytes, and for class switch recombination in mature B cells. The Ku heterodimer formed by Ku70 and Ku80 recognizes DSBs and facilitates the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, Paxx and Mri\/Cyren) and downstream core factor subunits X-ray repair cross-complementing group 4 (XRCC4), XRCC4-like factor (XLF), and DNA ligase 4 (Lig4). Accessory factors might be dispensable for the process, depending on the genetic background and DNA lesion type. To determine the physiological role of Mri in DNA repair and development, we introduced a frame-shift mutation in the Mri gene in mice. We then analyzed the development of Mri-deficient mice as well as wild type and immunodeficient controls. Mice lacking Mri possessed reduced levels of class switch recombination in B lymphocytes and slow proliferation of neuronal progenitors when compared to wild type littermates. Human cell lines lacking Mri were as sensitive to DSBs as the wild type controls. Overall, we concluded that Mri\/Cyren is largely dispensable for DNA repair and mouse development.<\/jats:p>","DOI":"10.3390\/biom9120798","type":"journal-article","created":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T10:54:10Z","timestamp":1574938450000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri\/Cyren"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-6788","authenticated-orcid":false,"given":"Sergio","family":"Casta\u00f1eda-Zegarra","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Huse","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8ystein","family":"R\u00f8sand","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sarno","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengtan","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Gago-Fuentes","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qindong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Alirezaylavasani","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"},{"name":"Molecular Biotechnology MS programme, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina-Beate","family":"Liabakk","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8759-1170","authenticated-orcid":false,"given":"Magnar","family":"Bj\u00f8r\u00e5s","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5088-3791","authenticated-orcid":false,"given":"Valentyn","family":"Oksenych","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway"},{"name":"St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway"},{"name":"Department of Biosciences and Nutrition (BioNut), Karolinska Institutet, 14183 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.dnarep.2014.01.010","article-title":"Functional overlaps between XLF and the ATM-dependent DNA double strand break response","volume":"16","author":"Kumar","year":"2014","journal-title":"DNA Repair (Amst)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10512","DOI":"10.1074\/jbc.TM117.000374","article-title":"Nonhomologous DNA end-joining for repair of DNA double-strand breaks","volume":"293","author":"Pannunzio","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Scully, R., Panday, A., Elango, R., and Willis, N.A. (2019). DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol.","DOI":"10.1038\/s41580-019-0152-0"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.molcel.2008.07.017","article-title":"Lymphocyte-specific compensation for XLF\/cernunnos end-joining functions in V(D)J recombination","volume":"31","author":"Li","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1128\/MCB.01057-12","article-title":"Cernunnos deficiency reduces thymocyte life span and alters the T cell repertoire in mice and humans","volume":"33","author":"Vera","year":"2013","journal-title":"Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/nature09604","article-title":"ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks","volume":"469","author":"Zha","year":"2011","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1073\/pnas.1121458109","article-title":"Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair","volume":"109","author":"Oksenych","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/cdd.2017.184","article-title":"PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice","volume":"25","author":"Abramowski","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1101\/gad.290510.116","article-title":"Synthetic lethality between PAXX and XLF in mammalian development","volume":"30","author":"Balmus","year":"2016","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.dnarep.2018.12.002","article-title":"Synthetic lethality between DNA repair factors Xlf and Paxx is rescued by inactivation of Trp53","volume":"73","author":"Xing","year":"2019","journal-title":"DNA Repair (Amst)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/2211-5463.12381","article-title":"Normal development of mice lacking PAXX, the paralogue of XRCC4 and XLF","volume":"8","author":"Xing","year":"2018","journal-title":"FEBS Open Bio"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13816","DOI":"10.1038\/ncomms13816","article-title":"PAXX promotes KU accumulation at DNA breaks and is essential for end-joining in XLF-deficient mice","volume":"8","author":"Liu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/S1097-2765(00)80264-6","article-title":"DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway","volume":"5","author":"Frank","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/35009138","article-title":"Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development","volume":"404","author":"Gao","year":"2000","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1073\/pnas.0915067107","article-title":"Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70","volume":"107","author":"Boboila","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1084\/jem.20092449","article-title":"Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4","volume":"207","author":"Boboila","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/S1568-7864(02)00151-9","article-title":"The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: Implications for unifying the heterogeneous phenotypes of NHEJ mutants","volume":"1","author":"Karanjawala","year":"2002","journal-title":"DNA Repair (Amst)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1073\/pnas.1222573110","article-title":"Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining","volume":"110","author":"Oksenych","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.dnarep.2017.07.008","article-title":"Synthetic lethality between murine DNA repair factors XLF and DNA-PKcs is rescued by inactivation of Ku70","volume":"57","author":"Xing","year":"2017","journal-title":"DNA Repair (Amst)"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.molcel.2018.06.018","article-title":"MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining","volume":"71","author":"Hung","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10529","DOI":"10.1038\/ncomms10529","article-title":"RAG2 and XLF\/Cernunnos interplay reveals a novel role for the RAG complex in DNA repair","volume":"7","author":"Lescale","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1083\/jcb.201808134","article-title":"XLF and H2AX function in series to promote replication fork stability","volume":"218","author":"Chen","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1073\/pnas.1120160109","article-title":"Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development","volume":"109","author":"Liu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cell.2013.01.007","article-title":"Mechanisms of programmed DNA lesions and genomic instability in the immune system","volume":"152","author":"Alt","year":"2013","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/bs.ai.2019.01.002","article-title":"Cis- and trans-factors affecting AID targeting and mutagenic outcomes in antibody diversification","volume":"141","author":"Yeap","year":"2019","journal-title":"Adv. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.dnarep.2018.08.019","article-title":"DNA double-strand breaks as drivers of neural genomic change, function, and disease","volume":"71","author":"Alt","year":"2018","journal-title":"DNA Repair (Amst)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15933","DOI":"10.1073\/pnas.0602674103","article-title":"Isolation, characterization, and genetic complementation of a cellular mutant resistant to retroviral infection","volume":"103","author":"Agarwal","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10950","DOI":"10.1074\/jbc.C113.533968","article-title":"A human short open reading frame (sORF)-encoded polypeptide that stimulates DNA end joining","volume":"289","author":"Slavoff","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11242","DOI":"10.1038\/ncomms11242","article-title":"The Ku-binding motif is a conserved module for recruitment and stimulation of non-homologous end-joining proteins","volume":"7","author":"Grundy","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nature24023","article-title":"Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN","volume":"549","author":"Arnoult","year":"2017","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S1097-2765(00)80271-3","article-title":"Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication","volume":"5","author":"Nilsen","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/2211-5463.12380","article-title":"Robust DNA repair in PAXX-deficient mammalian cells","volume":"8","author":"Dewan","year":"2018","journal-title":"FEBS Open Bio"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Xing, M., and Oksenych, V. (2019). Genetic interaction between DNA repair factors PAXX, XLF, XRCC4 and DNA-PKcs in human cells. FEBS Open Bio.","DOI":"10.1002\/2211-5463.12681"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1002\/stem.542","article-title":"Mitochondrial DNA integrity is essential for mitochondrial maturation during differentiation of neural stem cells","volume":"28","author":"Wang","year":"2010","journal-title":"Stem Cells"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/S1097-2765(02)00755-4","article-title":"Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice","volume":"10","author":"Rooney","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S1074-7613(00)80619-6","article-title":"A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination","volume":"9","author":"Gao","year":"1998","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S1074-7613(00)80386-6","article-title":"Growth retardation and leaky SCID phenotype of Ku70-deficient mice","volume":"7","author":"Gu","year":"1997","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/382551a0","article-title":"Requirement for Ku80 in growth and immunoglobulin V(D)J recombination","volume":"382","author":"Nussenzweig","year":"1996","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0092-8674(00)81714-6","article-title":"A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis","volume":"95","author":"Gao","year":"1998","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/24172","article-title":"Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV","volume":"396","author":"Frank","year":"1998","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1073\/pnas.051632098","article-title":"Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development","volume":"98","author":"Sekiguchi","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:38:15Z","timestamp":1760189895000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/12\/798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,28]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["biom9120798"],"URL":"https:\/\/doi.org\/10.3390\/biom9120798","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201911.0292.v1","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,28]]}}}