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We identified a germline single nucleotide polymorphism (SNP) in an intrinsically disordered region of the lysine demethylase KDM3C\/JMJD1C (p.S464T) that is associated with CRT outcomes in locally advanced rectal cancers (LARC) and head and neck squamous cell carcinoma (LA-HNSCC).\n                  <jats:italic>In silico<\/jats:italic>\n                  modeling with AlphaFold predicted S464T substitution influenced interaction between phosphorylated KDM3C and RNF8 FHA domain. In cellular models, conversion of S464 to T464 increased sensitivity to DNA-damaging agents. S464T substitution impaired damage-induced MDC1-RAP80 signaling and downstream RAP80-BRCA1 colocalization. SNP carrying cells impaired DNA repair causing genotoxic stress that is associated with increased cGAS-cGAMP innate immune signaling and increased apoptosis. Population analyses with the SNP highlighted an increase incidence of UV-induced skin and other cancers, linking inherited variation in the chromatin regulatory gene\n                  <jats:italic>KDM3C<\/jats:italic>\n                  to genome instability, cancer risk, and therapeutic vulnerability.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>\n                    We identify a germline polymorphism in\n                    <jats:italic>KDM3C<\/jats:italic>\n                    \/\n                    <jats:italic>JMJD1C<\/jats:italic>\n                    that disrupts DNA damage repair signaling and enhances sensitivity to DNA-damaging therapy. These findings reveal a mechanistic link between inherited variation in chromatin regulation and therapeutic response, providing a framework for biomarker-driven stratification of patients receiving chemoradiotherapy.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.26.26360896","type":"posted-content","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T18:45:25Z","timestamp":1788201925000},"source":"Crossref","is-referenced-by-count":0,"title":["A germline KDM3C polymorphism impairs DNA repair and sensitizes to chemoradiotherapy"],"prefix":"10.64898","author":[{"given":"Adria","family":"Hasan","sequence":"first","affiliation":[{"name":"Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V.","family":"Demidova","sequence":"additional","affiliation":[{"name":"Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, 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