{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:58:59Z","timestamp":1779364739900,"version":"3.53.0"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R56HL153068"],"award-info":[{"award-number":["R56HL153068"]}],"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":["R01HL15306801"],"award-info":[{"award-number":["R01HL15306801"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Michigan Cancer Center","award":["P30CA046592"],"award-info":[{"award-number":["P30CA046592"]}]},{"name":"University of Michigan Transgenic Animal Model Core"},{"name":"Program in Biomedical Sciences"},{"DOI":"10.13039\/100008455","name":"University of Michigan Medical School","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008455","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The MRE11\/RAD50\/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.<\/jats:p>","DOI":"10.1093\/hmg\/ddae101","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T13:00:04Z","timestamp":1718715604000},"page":"1605-1617","source":"Crossref","is-referenced-by-count":5,"title":["Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder"],"prefix":"10.1093","volume":"33","author":[{"given":"Andrea J","family":"Hartlerode","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200 , United States"},{"name":"Department of Human Genetics, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed M","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200 , United States"},{"name":"Department of Biochemistry , Faculty of Pharmacy, , Organization of African Unity Street, Cairo , Egypt 11566"},{"name":"Ain Shams University , Faculty of Pharmacy, , Organization of African Unity Street, Cairo , Egypt 11566"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven K","family":"Orban","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Benedeck","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200 , United States"},{"name":"Program in Biomedical Sciences PhD Program, University of Michigan Medical School , 1135 Catherine Street, Rm 2960, Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koral","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200 , United States"},{"name":"Program in Biomedical Sciences PhD Program, University of Michigan Medical School , 1135 Catherine Street, Rm 2960, Ann Arbor, MI 48109 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Hoenerhoff","sequence":"additional","affiliation":[{"name":"In Vivo Animal Core , Unit for Laboratory Animal Medicine, , 2800 Plymouth Road, Ann Arbor, MI 48109 , United States"},{"name":"University of Michigan Medical 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