{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T21:18:11Z","timestamp":1793395091399,"version":"4.5.0"},"posted":{"date-parts":[[2025,7,18]]},"group-title":"Genetics","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 HL15306801"],"award-info":[{"award-number":["R01 HL15306801"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 CA046592"],"award-info":[{"award-number":["P30 CA046592"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The MRE11 DNA nuclease plays central roles in the repair of DNA double-strand breaks (DSBs) as a core component of the heterotrimeric MRE11\/RAD50\/NBS1 (MRN) complex. MRN localizes to chromosomal DSBs and recruits and activates the apical DSB repair protein kinase, ATM, which phosphorylates downstream substrates to elicit cellular DNA damage responses. Pathogenic variants in\n                  <jats:italic>MRE11<\/jats:italic>\n                  cause the genome instability disorder ataxia-telangiectasia-like disorder (ATLD). The first ATLD patient allele identified,\n                  <jats:italic>ATLD1<\/jats:italic>\n                  , is a nonsense mutation that deletes 76 amino acids from the MRE11 C-terminus and results in markedly reduced levels of MRE11-ATLD1 and the entire MRN complex. This region of the C-terminus has been demonstrated to function in DNA binding, mediate functional protein interactions, and undergo post-translational modifications that regulate MRE11 nucleolytic activities. We previously demonstrated that transgenic mice expressing low wildtype MRN exhibit severe phenotypes, including small body size, anemia, and cellular DNA DSB repair defects. Thus, it is currently unknown whether reduced MRE11-ATLD1 and MRN levels, loss of the C-terminus, or both cause disease-associated phenotypes. In this study, we generated transgenic mouse models that express near endogenous or significantly reduced levels of MRE11-ATLD1 to determine the\n                  <jats:italic>in vivo<\/jats:italic>\n                  importance of the MRE11 C-terminus. We observe that reduced MRE11-ATLD1 expression leads to anemia, bone marrow failure, extramedullary hematopoiesis, and impaired lymphocyte development, similar to mice expressing low wildtype MRE11. In contrast, higher expression of MRE11-ATLD1 results in a subset of moderate phenotypes, indicating that loss of C-terminus has limited impact on MRN functions\n                  <jats:italic>in vivo<\/jats:italic>\n                  . These findings have implications for clinical predictions of ATLD patients harboring pathogenic\n                  <jats:italic>MRE11<\/jats:italic>\n                  variants that impair MRE11 function and\/or impact MRN protein levels.\n                <\/jats:p>","DOI":"10.1101\/2025.07.15.664809","type":"posted-content","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T00:05:18Z","timestamp":1752883518000},"source":"Crossref","is-referenced-by-count":1,"title":["Differential expression of a disease-associated\n                  <i>MRE11<\/i>\n                  variant reveals distinct phenotypic outcomes"],"prefix":"10.64898","author":[{"given":"McKenna B.","family":"DeFoer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M.","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J.","family":"Hartlerode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven K.","family":"Orban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keegan","family":"McDonough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Quirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna K.L.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David O.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-4258","authenticated-orcid":false,"given":"JoAnn M.","family":"Sekiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072213250782000_2025.07.15.664809v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81547-0"},{"key":"2025072213250782000_2025.07.15.664809v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00394-2"},{"key":"2025072213250782000_2025.07.15.664809v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.08.017"},{"key":"2025072213250782000_2025.07.15.664809v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00381-1"},{"key":"2025072213250782000_2025.07.15.664809v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.12.003"},{"key":"2025072213250782000_2025.07.15.664809v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1639"},{"key":"2025072213250782000_2025.07.15.664809v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1641"},{"key":"2025072213250782000_2025.07.15.664809v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1640"},{"key":"2025072213250782000_2025.07.15.664809v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1175"},{"key":"2025072213250782000_2025.07.15.664809v1.10","doi-asserted-by":"crossref","unstructured":"Ceccaldi, R. and Cejka, P. (2025) Mechanisms and regulation of DNA end resection in the maintenance of genome stability. Nat Rev Mol Cell Biol, in press.","DOI":"10.1038\/s41580-025-00841-4"},{"key":"2025072213250782000_2025.07.15.664809v1.11","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jns.2013.11.032","article-title":"Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia","volume":"337","year":"2014","journal-title":"J Neurol Sci"},{"key":"2025072213250782000_2025.07.15.664809v1.12","doi-asserted-by":"crossref","unstructured":"Rahman, S. , Canny, M.D. , Buschmann, T.A. and Latham, M.P . (2020) A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex. Cells, 9.","DOI":"10.3390\/cells9071678"},{"key":"2025072213250782000_2025.07.15.664809v1.13","first-page":"1830","article-title":"Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?","volume":"164A","year":"2014","journal-title":"Am J Med Genet A"},{"key":"2025072213250782000_2025.07.15.664809v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2010.12.002"},{"key":"2025072213250782000_2025.07.15.664809v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2009.02.037"},{"key":"2025072213250782000_2025.07.15.664809v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh221"},{"key":"2025072213250782000_2025.07.15.664809v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.04.010"},{"key":"2025072213250782000_2025.07.15.664809v1.18","doi-asserted-by":"crossref","first-page":"10121","DOI":"10.1038\/s41598-018-28370-5","article-title":"Reversible mislocalization of a disease-associated MRE11 splice variant product","volume":"8","year":"2018","journal-title":"Sci Rep"},{"key":"2025072213250782000_2025.07.15.664809v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00455-6"},{"key":"2025072213250782000_2025.07.15.664809v1.20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808906200"},{"key":"2025072213250782000_2025.07.15.664809v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.10.017"},{"key":"2025072213250782000_2025.07.15.664809v1.22","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/j.molcel.2024.05.019","article-title":"Molecular insights into the activation of Mre11-Rad50 endonuclease activity by Sae2\/CtIP","volume":"84","year":"2024","journal-title":"Mol Cell"},{"key":"2025072213250782000_2025.07.15.664809v1.23","doi-asserted-by":"crossref","unstructured":"Salifou, K. , Burnard, C. , Basavarajaiah, P. , Grasso, G. , Helsmoortel, M. , Mac, V. , Depierre, D. , Franckhauser, C. , Beyne, E. , Contreras, X. et al. (2021) Chromatin-associated MRN complex protects highly transcribing genes from genomic instability. Sci Adv, 7.","DOI":"10.1126\/sciadv.abb2947"},{"key":"2025072213250782000_2025.07.15.664809v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.022"},{"key":"2025072213250782000_2025.07.15.664809v1.25","doi-asserted-by":"crossref","first-page":"e2422720122","DOI":"10.1073\/pnas.2422720122","article-title":"ATM priming and end resection-coupled phosphorylation of MRE11 is important for fork protection and replication restart","volume":"122","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025072213250782000_2025.07.15.664809v1.26","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1093\/hmg\/ddae101","article-title":"Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder","volume":"33","year":"2024","journal-title":"Hum Mol Genet"},{"key":"2025072213250782000_2025.07.15.664809v1.27","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1001\/jama.2024.25349","article-title":"Essential Thrombocythemia: A Review","volume":"333","year":"2025","journal-title":"JAMA"},{"key":"2025072213250782000_2025.07.15.664809v1.28","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-7-13"},{"key":"2025072213250782000_2025.07.15.664809v1.29","doi-asserted-by":"crossref","first-page":"101225","DOI":"10.1016\/j.blre.2024.101225","article-title":"Longitudinal clinical manifestations of Fanconi anemia: A systematized review","volume":"68","year":"2024","journal-title":"Blood Rev"},{"key":"2025072213250782000_2025.07.15.664809v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/nri3570"},{"key":"2025072213250782000_2025.07.15.664809v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2021.10.002"},{"key":"2025072213250782000_2025.07.15.664809v1.32","doi-asserted-by":"crossref","unstructured":"Cenariu, D. , Iluta, S. , Zimta, A.A. , Petrushev, B. , Qian, L. , Dirzu, N. , Tomuleasa, C. , Bumbea, H. and Zaharie, F . (2021) Extramedullary Hematopoiesis of the Liver and Spleen. J Clin Med, 10.","DOI":"10.3390\/jcm10245831"},{"key":"2025072213250782000_2025.07.15.664809v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2212"},{"key":"2025072213250782000_2025.07.15.664809v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3546"},{"key":"2025072213250782000_2025.07.15.664809v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3072"},{"key":"2025072213250782000_2025.07.15.664809v1.36","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111.23.3497"},{"key":"2025072213250782000_2025.07.15.664809v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.08.015"},{"key":"2025072213250782000_2025.07.15.664809v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108559"},{"key":"2025072213250782000_2025.07.15.664809v1.39","doi-asserted-by":"crossref","unstructured":"Takagi, M. , Hoshino, A. , Bousset, K. , Roddecke, J. , Martin, H.L. , Folcut, I. , Tomomasa, D. , Yang, X. , Kobayashi, J. , Sakata, N. , et al. (2023) Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants. J Clin Immunol, in press.","DOI":"10.1007\/s10875-023-01591-8"},{"key":"2025072213250782000_2025.07.15.664809v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.11.040"},{"key":"2025072213250782000_2025.07.15.664809v1.41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s12276-024-01192-4","article-title":"Extramedullary hematopoiesis in cancer","volume":"56","year":"2024","journal-title":"Exp Mol Med"},{"key":"2025072213250782000_2025.07.15.664809v1.42","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1007\/s00439-022-02462-9","article-title":"Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair","volume":"141","year":"2022","journal-title":"Hum Genet"},{"key":"2025072213250782000_2025.07.15.664809v1.43","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5498.1962"},{"key":"2025072213250782000_2025.07.15.664809v1.44","doi-asserted-by":"publisher","DOI":"10.1101\/gad.956902"},{"key":"2025072213250782000_2025.07.15.664809v1.45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081326"},{"key":"2025072213250782000_2025.07.15.664809v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.03.009"},{"key":"2025072213250782000_2025.07.15.664809v1.47","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00917-10"},{"key":"2025072213250782000_2025.07.15.664809v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.21.6412"},{"key":"2025072213250782000_2025.07.15.664809v1.49","doi-asserted-by":"crossref","first-page":"5759","DOI":"10.1038\/s41467-023-41544-8","article-title":"Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice","volume":"14","year":"2023","journal-title":"Nat Commun"},{"key":"2025072213250782000_2025.07.15.664809v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00747-X"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.15.664809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:58:29Z","timestamp":1782277109000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.15.664809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":50,"URL":"https:\/\/doi.org\/10.1101\/2025.07.15.664809","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1093\/hmg\/ddaf154","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,7,18]]},"subtype":"preprint"}}