DNA靶向药物广泛用于抗癌治疗。许多这些药物会引起不同类型的 DNA 损伤，即 DNA 分子化学结构的改变。然而，与 DNA 结合的分子也可能干扰 DNA 堆积到染色质中。有趣的是，一些分子不会引起 DNA 化学结构的任何变化，但会干扰 DNA 与组蛋白的结合和核小体包裹。这导致染色质组蛋白丢失和核小体不稳定，这种现象我们称为染色质损伤。尽管细胞对 DNA 损伤的反应已得到充分研究，但染色质损伤的后果却没有得到充分研究。此外，许多用于研究DNA损伤的药物也会引起染色质损伤，因此尚不清楚哪些影响是由DNA损伤引起的，还是由染色质损伤引起的。在这项研究中，我们旨在澄清这个问题。我们用博莱霉素（一种模拟核酸酶的药物，主要切割无核小体的 DNA，从而以 DNA 断裂的形式引起 DNA 损伤）和 CBL0137 治疗正常细胞和肿瘤细胞，CBL0137 会导致染色质损伤，但不会直接损伤 DNA。我们描述了 DNA 和染色质损伤后果之间的异同。这两种药物对肿瘤的毒性都比正常细胞更大，虽然 DNA 损伤会导致正常细胞和肿瘤细胞衰老，但染色质损伤却不会。两种药物均激活 p53，但染色质损伤导致未修饰 p53 水平升高，其转录活性与 DNA 损伤激活的 p53 相似或更低。最重要的是，我们发现，虽然 DNA 损伤引起的转录变化受到少数 p53 靶标的 p53 依赖性激活的限制，但染色质损伤以 p53 独立的方式激活了多倍的基因。© 作者 2023。出版者牛津大学出版社代表核酸研究。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.