medRxiv : the preprint server for health sciences · 2026
A germline KDM3C polymorphism impairs DNA repair and sensitizes to chemoradiotherapy.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Hasan Adria, Demidova Elena V, Priyadarshini Pragya, Czyzewicz Philip, Gathuka Leonny, Murayama Takahiko, Zhou Yan, Kiss Zachary Ac, Shastry Raksha Kr, Andrake Mark, Hearne Gavin, Devarajan Karthik, Wu Chao, Shah Anshul, Schultz Bryant M, Connolly Denise C, Rosen Gail L, Canadas Israel, Liu Jeffrey C, Burtness Barbara A, Smith Jesse Joshua, Dunbrack Roland L, Golemis Erica A, Whetstine Johnathan R, Meyer Joshua E, Arora Sanjeevani
Аннотация
Chemoradiotherapy (CRT) is the standard-of-care therapy for many solid malignancies, yet predictive biomarkers of treatment response remain limited. 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). In silico 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 KDM3C to genome instability, cancer risk, and therapeutic vulnerability.