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 Canadas, Jeffrey C Liu, Barbara A Burtness, Jesse Joshua Smith, Roland L Dunbrack, Erica A Golemis, Johnathan R Whetstine, Joshua E Meyer, Sanjeevani Arora
Published in
medRxiv : the preprint server for health sciences. Aug 31, 2026. Epub Aug 31, 2026.
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.
PMID:
42732193
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.
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