Induction of secondary leukemias by chemotherapy-based cancer treatment represents a serious side effect that frequently involves endonuclease G (EndoG)-mediated chromosomal rearrangements at the mixed-lineage leukemia (MLL) gene. The applicants identified peptides antagonizing such rearrangements and found that they differentially affect MLL binding of EndoG, which operates in mitochondria in unstressed cells. In the 2^nd funding period, they will characterize differences in peptide mode-of-action on nuclear and mitochondrial genomes and consider organelle-specific therapeutic applications. Other goals are to understand structure-based traits facilitating EndoG interactions with MLL and the effects of peptides on fragile sites other than MLL.