A germline KDM3C polymorphism impairs DNA repair and sensitizes to chemoradiotherapy
Year: 2026
Type: preprint
Abstract: 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. Statement of Significance We identify a germline polymorphism in KDM3C / JMJD1C 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.
Source: medRxiv
Authors: Adria Hasan, Elena V. Demidova, Pragya Priyadarshini, Philip Czyzewicz, Leonny Gathuka, Takahiko Murayama, Yan Zhou, Zachary AC Kiss, Raksha KR Shastry, Mark Andrake, Gavin Hearne, Karthik Devarajan, Chao Wu, Anshul Shah, Bryant M. Schultz, Denise C. Connolly, Gail L. Rosen, Israel Cañadas, Jeffrey C. Liu, Barbara A. Burtness, J Joshua Smith, Roland L. Dunbrack, Erica A. Golemis, Johnathan R. Whetstine, Joshua E. Meyer, Sanjeevani Arora
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204763918
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