{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:10:15Z","timestamp":1778479815857,"version":"3.51.4"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007197","name":"United States Public Health Service","doi-asserted-by":"publisher","award":["R01 CA258519"],"award-info":[{"award-number":["R01 CA258519"]}],"id":[{"id":"10.13039\/100007197","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The DNA mismatch repair protein MSH3 reversibly shifts from nucleus to the cytosol upon IL-6 signaling, abrogating the repair function of the MSH3-MSH2 heterodimer in the nucleus and increases aggressiveness and metastasis potential of colorectal cancers. A polymorphism proximate to MSH3\u2019s nuclear localization signal (NLS), \u039427bpMSH3, alters NLS function such that IL-6 triggers \u039427bpMSH3 accumulation in the cytosol. Public databases indicate \u039427bpMSH3 is rare in the germline yet we previously identified its presence in half of colon cancer cell lines tested and 19% of ulcerative colitis (UC) tissue samples. Here in examining ~\u2009200 each of UC, early-onset (eo)CRC, and late-onset (lo)CRC patients, biallelic MSH3 NLS germline polymorphisms were exclusively present in 15% of controls but in 18% of UC and 17% of eoCRC patients and were higher among CRC stage 3\/4 patients compared to stage 2 patients; these marginal increases could potentiate inflammation-to-cancer transformation and\/or metastatic disease. Using cell models we demonstrate IL-6-induced binding of wild type and \u039427bpMSH3 to the NF\u03baB activating complex NEMO\/IKK\u03b3 which stabilizes MSH3 after disengaging from its nuclear partner MSH2, linking inflammation with DNA repair protein stability. Additional NLS modifications using MSH3-FLAG mimics cytosolic \u039427bpMSH3 retention to cause loss-of-function after inflammation.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf181","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T12:59:07Z","timestamp":1763211547000},"source":"Crossref","is-referenced-by-count":0,"title":["Prevalence of germline\n                    <i>MSH3<\/i>\n                    polymorphisms in ulcerative colitis and early-onset colorectal cancer patients that potentiates inflammation-to-cancer transformation"],"prefix":"10.1093","volume":"35","author":[{"given":"Stephanie S","family":"Tseng-Rogenski","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, MI 48109 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anand","family":"Venugopal","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, MI 48109 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minoru","family":"Koi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, MI 48109 ,","place":["United States"]},{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego , 9500 Gilman Drive, San Diego, CA 92093 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2623-7332","authenticated-orcid":false,"given":"John M","family":"Carethers","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan , 1500 E. Medical Center Drive, Ann Arbor, MI 48109 ,","place":["United States"]},{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego , 9500 Gilman Drive, San Diego, CA 92093 ,","place":["United States"]},{"name":"Moores Cancer Center, University of California San Diego , 9500 Gilman Drive, San Diego, CA 92093 ,","place":["United States"]},{"name":"Herbert Wertheim School of Public Health and Longevity Science, University of California San Diego , 9500 Gilman Drive, San Diego, CA 92093 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"2026051101321145700_ref1","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1053\/j.gastro.2008.07.076","article-title":"Genomic and epigenetic instability in colorectal cancer 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