Cancer mutations in histone H3 cause severe genome stability defects, although the mechanisms affected remain to be fully elucidated. In this new study, we show that the oncohistone H3K27M (lysine 27-to-methionine mutation on histone H3) disrupts the chromatin-based regulation of the conserved TSK/TONSL-H3.1 pathway, resulting in a DNA repair pathway that becomes a DNA-damaging agent. By using the plant Arabidopsis as a model, we reveal a new mechanism with relevance to a pediatric brain cancer.