A germline KDM3C polymorphism impairs DNA repair and sensitizes to chemoradiotherapy
Hasan, A.; Demidova, E. V.; Priyadarshini, P.; Czyzewicz, P.; Gathuka, L.; Murayama, T.; Zhou, Y.; Kiss, Z. A.; Shastry, R. K.; Andrake, M.; Hearne, G.; Devarajan, K.; Wu, C.; Shah, A.; Schultz, B. M.; Connolly, D. C.; Rosen, G. L.; Canadas, I.; Liu, J. C.; Burtness, B. A.; Smith, J. J.; Dunbrack, R. L.; Golemis, E. A.; Whetstine, J. R.; Meyer, J. E.; Arora, S.
Show 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.
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