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Figure 2. Curaxins affect different levels of chromatin structure. A proposed sequence of events during incubation of cancer cells with curaxins. Upper part: initially, curaxins induce time- and concentration-dependent FACT trapping on the unfolded nucleosomes. As curaxins intercalate into DNA, they induce progressive, FACT-dependent unfolding of nucleosomes that could eventually lead to eviction of core histones. Lower part: in parallel with the changes in the nucleosome structure, the higher-order chromatin structure is dramatically disturbed. Curaxins induce changes in the structure of internucleosomal linker DNA, releasing linker histones, unfolding the chromatin fiber, causing displacement of CTCF factor from DNA, and disrupting existing chromatin domain boundaries. Taken together, these changes in the structure of nucleosomes, chromatin fibers, and global three-dimensional chromatin organization lead to a large-scale loss of chromatin integrity and cancer cell death. Components are modeled as in Figure 1, with the addition of PDB 1Y1V (RNA polymerase II elongation complex structure). FACT: facilitates chromatin transcription; CTCF: CCCTC-binding factor