Comparison of cell response to chromatin and DNA damage.

Abstract

DNA-targeting drugs are widely used for anti-cancer treatment. Many of these drugs cause different types of DNA damage, i.e. alterations in the chemical structure of DNA molecule. However, molecules binding to DNA may also interfere with DNA packing into chromatin. Interestingly, some molecules do not cause any changes in DNA chemical structure but interfere with DNA binding to histones and nucleosome wrapping. This results in histone loss from chromatin and destabilization of nucleosomes, a phenomenon that we call chromatin damage. Although the cellular response to DNA damage is well-studied, the consequences of chromatin damage are not. Moreover, many drugs used to study DNA damage also cause chromatin damage, therefore there is no clarity on which effects are caused by DNA or chromatin damage. In this study, we aimed to clarify this issue. We treated normal and tumor cells with bleomycin, nuclease mimicking drug which cut predominantly nucleosome-free DNA and therefore causes DNA damage in the form of DNA breaks, and CBL0137, which causes chromatin damage without direct DNA damage. We describe similarities and differences between the consequences of DNA and chromatin damage. Both agents were more toxic for tumor than normal cells, but while DNA damage causes senescence in both normal and tumor cells, chromatin damage does not. Both agents activated p53, but chromatin damage leads to the accumulation of higher levels of unmodified p53, which transcriptional activity was similar to or lower than that of p53 activated by DNA damage. Most importantly, we found that while transcriptional changes caused by DNA damage are limited by p53-dependent activation of a small number of p53 targets, chromatin damage activated many folds more genes in p53 independent manner.