{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T22:16:07Z","timestamp":1794608167996,"version":"4.9.1"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,7,4]],"date-time":"2018-07-04T00:00:00Z","timestamp":1530662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ataxia-telangiectasia (AT) and related disorders feature cancer predisposition, neurodegeneration, and immunodeficiency resulting from failure to respond to DNA damage. Hypomorphic mutations in <jats:italic>MRE11<\/jats:italic> cause an AT-like disorder (ATLD) with variable clinical presentation. We have sought to understand how diverse <jats:italic>MRE11<\/jats:italic> mutations may provide unique therapeutic opportunities, and potentially correlate with clinical variability. Here we have undertaken studies of an <jats:italic>MRE11<\/jats:italic> splice site mutation that was found in two ATLD siblings that died of pulmonary adenocarcinoma at the young ages of 9 and 16. The mutation, termed <jats:italic>MRE11<\/jats:italic> alternative splice mutation (<jats:italic>MRE11<\/jats:italic><jats:sup>ASM<\/jats:sup>), causes skipping of a highly conserved exon while preserving the protein\u2019s open reading frame. A new mouse model expressing <jats:italic>Mre11<\/jats:italic><jats:sup>ASM<\/jats:sup> from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the <jats:italic>MRE11<\/jats:italic><jats:sup>ATLD1<\/jats:sup> mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11<jats:sup>ASM<\/jats:sup> is mislocalized to the cytoplasm, in contrast to MRE11<jats:sup>ATLD1<\/jats:sup>, which remains nuclear. Strikingly, MRE11<jats:sup>ASM<\/jats:sup> mislocalization is corrected by inhibition of the proteasome, implying that the protein undergoes strict protein quality control in the nucleus. These findings raise the prospect that inhibition of poorly understood nuclear protein quality control mechanisms might have therapeutic benefit in genetic disorders causing cytoplasmic mislocalization.<\/jats:p>","DOI":"10.1038\/s41598-018-28370-5","type":"journal-article","created":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T13:52:39Z","timestamp":1530193959000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reversible mislocalization of a disease-associated MRE11 splice variant product"],"prefix":"10.1038","volume":"8","author":[{"given":"Andrea J.","family":"Hartlerode","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Regal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David O.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,7,4]]},"reference":[{"key":"28370_CR1","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1146\/annurev.genom.7.080505.115648","volume":"8","author":"PJ McKinnon","year":"2007","unstructured":"McKinnon, P. J. & Caldecott, K. W. DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 8, 37\u201355, https:\/\/doi.org\/10.1146\/annurev.genom.7.080505.115648 (2007).","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"28370_CR2","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1146\/annurev-biochem-060614-034335","volume":"84","author":"TT Paull","year":"2015","unstructured":"Paull, T. T. Mechanisms of ATM Activation. Annual review of biochemistry 84, 711\u2013738, https:\/\/doi.org\/10.1146\/annurev-biochem-060614-034335 (2015).","journal-title":"Annual review of biochemistry"},{"key":"28370_CR3","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/nsmb.3072","volume":"22","author":"AJ Hartlerode","year":"2015","unstructured":"Hartlerode, A. J., Morgan, M. J., Wu, Y., Buis, J. & Ferguson, D. O. Recruitment and activation of the ATM kinase in the absence of DNA-damage sensors. 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