{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:46:11Z","timestamp":1791589571750,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,6,9]],"date-time":"2008-06-09T00:00:00Z","timestamp":1212969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2008,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The loss of DNA mismatch repair (MMR) is responsible for hereditary nonpolyposis colorectal cancer and a subset of sporadic tumors. Acquired resistance or tolerance to some anti\u2010cancer drugs occurs when MMR function is impaired. 5\u2010Fluorouracil (FU), an anti\u2010cancer drug used in the treatment of advanced colorectal and other cancers, and its metabolites are incorporated into RNA and DNA and inhibit thymidylate synthase resulting in depletion of dTTP and incorporation in DNA of uracil. Although the MMR deficiency has been implicated in tolerance to FU, the mechanism of cell killing remains unclear. Here, we examine the cellular response to fluorodeoxyuridine (FdU) and the role of the MMR system. After brief exposure of cells to low doses of FdU, MMR mediates DNA damage signaling during S\u2010phase and triggers arrest in G2\/M in the first cell cycle in a manner requiring MutS\u03b1, MutL\u03b1, and DNA replication. Cell cycle arrest is mediated by ATR kinase and results in phosphorylation of Chk1 and SMC1. MutS\u03b1 binds FdU:G mispairs in vitro consistent with its being a DNA damage sensor. Prolonged treatment with FdU results in an irreversible arrest in G2 that is independent of MMR status and leads to the accumulation of DNA lesions that are targeted by the base excision repair (BER) pathway. Thus, MMR can act as a direct sensor of FdU\u2010mediated DNA lesions eliciting cell cycle arrest via the ATR\/Chk1 pathway. However, at higher levels of damage, other damage surveillance pathways such as BER also play important roles. J. Cell. Biochem. 105: 245\u2013254, 2008. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.21824","type":"journal-article","created":{"date-parts":[[2008,6,9]],"date-time":"2008-06-09T10:53:23Z","timestamp":1213008803000},"page":"245-254","source":"Crossref","is-referenced-by-count":45,"title":["The mismatch repair\u2010mediated cell cycle checkpoint response to fluorodeoxyuridine"],"prefix":"10.1002","volume":"105","author":[{"given":"Angen","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken\u2010ichi","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Salerno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,8,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2960"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh347"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3969"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-1030"},{"key":"e_1_2_6_6_1","first-page":"5773","article-title":"Selective radiosensitization of drug\u2010resistant MutS homologue\u20102 (MSH2) mismatch repair\u2010deficient cells by halogenated thymidine (dThd) analogues: Msh2 mediates dThd analogue DNA levels and the differential cytotoxicity and cell cycle effects of the dThd analogues and 6\u2010thioguanine","volume":"60","author":"Berry SE","year":"2000","journal-title":"Cancer Res"},{"key":"e_1_2_6_7_1","first-page":"5490","article-title":"Role of MutSalpha in the recognition of iododeoxyuridine in DNA","volume":"63","author":"Berry SE","year":"2003","journal-title":"Cancer 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microsatellite instability and reduces N\u2010methyl\u2010N'\u2010nitro\u2010N\u2010nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation","volume":"54","author":"Koi M","year":"1994","journal-title":"Cancer Res"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.74.082803.133243"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00384-006-0131-8"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2957"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700235"},{"key":"e_1_2_6_23_1","doi-asserted-by":"crossref","first-page":"5252","DOI":"10.1016\/S0021-9258(18)89014-7","article-title":"A new approach to the study of the base\u2010excision repair pathway using methoxyamine","volume":"260","author":"Liuzzi M","year":"1985","journal-title":"J Biol 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