Genome-wide CRISPR-screening identifies p53 as regulator of cancer cell sensitivity to the histone evicting anthracycline aclarubicin

Abstract

The anthracycline family, with its prime member doxorubicin, is one of the cornerstones in cancer chemotherapy and acts by poisoning topoisomerase II, resulting in DNA double-stranded breaks. One of its members, aclarubicin, is considered a distinct member of this family due to its inability to inflict DNA double-strand breaks. Despite this, aclarubicin is an effective anti-cancer drug by evicting histones, resulting in chromatin damage. How aclarubicin-induced chromatin damage induces cell death remains largely unknown. Here, we performed a genome-wide CRISPR screen to identify factors regulating sensitivity of cells to aclarubicin and identified p53 as a critical factor for cellular sensitivity. Even though aclarubicin does not induce DNA breaks, treatment resulted in swift activation of ATM independent of the MRN complex, which stabilized and activated p53, resulting in apoptosis and cell cycle arrest. Furthermore, response to aclarubicin treatment could reasonably be predicted by the p53-status of cell lines. These data suggest that ATM and p53 can be activated for apoptosis induction by at least two different pathways, DNA- and chromatin damage. Together, these data suggest p53 could be an important factor to stratify patients for treatment with Aclarubicin.