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However, how aberrant Wnt\/\u03b2-catenin signaling enables colorectal cancer cells to tolerate chemotherapy-induced DNA damage remains elusive. Identifying actionable downstream effectors of this pathway may provide a more selective strategy to improve chemotherapy response while avoiding the toxicity associated with global Wnt inhibition. Here we show that\n                    <jats:italic>TELO2-interacting protein 1<\/jats:italic>\n                    (\n                    <jats:italic>TTI1<\/jats:italic>\n                    ) is a direct transcriptional target of \u03b2-catenin\/TCF in colorectal cancer. TTI1 expression correlates with \u03b2-catenin abundance and is elevated in tumors from patients with poor response to neoadjuvant chemotherapy. Mechanistically, TTI1 maintains the integrity of the TELO2-TTI1-TTI2 complex and stabilizes the DNA damage response kinases ATM and ATR. Genetic depletion of TTI1 destabilizes ATM and ATR, attenuates DNA damage signaling, impairs double-strand break repair, and sensitizes colorectal cancer cells to 5-fluorouracil and oxaliplatin. Conversely, restoration of TTI1 or ATM\/ATR re-establishes DNA damage responses and chemo-insensitivity. Pharmacological suppression of the TTT complex by piperlongumine mimics TTI1 loss and enhances the anti-tumor activity of chemotherapy in cell lines, xenografts,\n                    <jats:italic>Apc<\/jats:italic>\n                    -mutant patient-derived organoids and\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>min\/+<\/jats:sup>\n                    colonic adenomas. These findings define a \u03b2-catenin-TTI1-ATM\/ATR axis that links Wnt\/\u03b2-catenin activation to DNA damage tolerance and chemotherapy response in colorectal cancer. Targeting TTI1 is therefore a promising approach to improve chemotherapy efficacy in Wnt\/\u03b2-catenin-activated colorectal cancer.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00475-8","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:02:50Z","timestamp":1781236970000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TELO2-interacting protein 1 (TTI1), a novel Wnt\/\u03b2-catenin target gene, decreases chemo-sensitivity in colorectal cancer by modulating DNA damage responses"],"prefix":"10.1186","volume":"7","author":[{"given":"Yuqiao","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengbo","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-5352","authenticated-orcid":false,"given":"Kai","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"issue":"1","key":"475_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","volume":"72","author":"RL Siegel","year":"2022","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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All patients signed an informed consent to participate in the study before sample donation. The study was reviewed and approved by the Ethical Committee of Xiangya Hospital (Approval No. 202103507) and conducted in accordance with the principles of the Helsinki Declaration.Animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Hunan SJA Laboratory Animal Co., Ltd. (Approval No. IACUC-SJA2022107-2). The ethics committee permitted a maximum tumor burden of 1,000\u202fmm\n                      3\n                      , which was not exceeded in any experimental animals. All experiments were performed in strict accordance with this approved protocol, and the maximal tumor burden was not exceeded in any animal during the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"88"}}