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Among these, F102C and F133L are frequent prostate cancer mutations within the substrate\u2010binding domain, yet their biochemical consequences remain incompletely understood. Using quantitative proteomics, we show that SPOP\u2010F133L, unlike SPOP\u2010F102C, retains degradative activity toward the nuclear basket proteins NUP153 and TPR, indicating substrate\u2010dependent loss\u2010of\u2010function. Moreover, SPOP\u2010F133L induces partial down\u2010regulation of p53 through a Cullin\u2010RING ligase\u2010dependent, post\u2010translational mechanism, revealing a potential neo\u2010substrate relationship. Finally, we demonstrate that both SPOP\u2010F102C and SPOP\u2010F133L support targeted protein degradation in an engineered cellular system. These findings define the degradative capacities of SPOP mutants and highlight opportunities to repurpose these variants as mutant\u2010selective E3 ligases for therapeutic applications.<\/jats:p>","DOI":"10.1002\/cbic.202500914","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T13:37:06Z","timestamp":1768397826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systematic Characterization of Cancer\u2010Associated SPOP Mutants Reveals Novel and Reprogrammable Degradative Activities"],"prefix":"10.1002","volume":"27","author":[{"given":"Alana G.","family":"Caldwell","sequence":"first","affiliation":[{"name":"Interdisciplinary Biological Sciences Graduate Program Northwestern University  Evanston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshil","family":"Parmar","sequence":"additional","affiliation":[{"name":"Department of Chemistry Northwestern University  Evanston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Chemistry Northwestern University  Evanston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry Northwestern University  Evanston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0951-9664","authenticated-orcid":false,"given":"Xiaoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Interdisciplinary Biological Sciences Graduate Program Northwestern University  Evanston USA"},{"name":"Department of Chemistry Northwestern University  Evanston USA"},{"name":"Chemistry of Life Processes Institute Northwestern University  Evanston USA"},{"name":"Robert H. 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