Genome-wide CRISPR-screening identifies p53 as regulator of cancer cell sensitivity to the histone evicting anthracycline aclarubicin.
5 affiliations
- 1Department of Cell and Chemical Biology, ONCODE institute, Leiden University Medical Center, Leiden, The Netherlands. [email protected].
- 2Department of Cell and Chemical Biology, ONCODE institute, Leiden University Medical Center, Leiden, The Netherlands.
- 3Ben Towne Center, Seattle Children's Research Institute, Seattle, Washington and Department of Pediatrics, University of Washington, Seattle, WA, USA.
- 4Alzheimer Center Amsterdam, department of Neurology, Amsterdam Neuroscience Amsterdam, University Medical Center Amsterdam, Amsterdam, The Netherlands.
- 5Department of Cell and Chemical Biology, ONCODE institute, Leiden University Medical Center, Leiden, The Netherlands. [email protected].
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.
Related
- 321 Genome-scale CRISPR KO screen identifies PCBP2 as a tumor-intrinsic regulator of cancer cell sensitivity to human CD4+ T cell killing
- Pan-Cancer Analysis Identifies LUC7L2 as a Prognostic Biomarker and Potential Functional Regulator of Prostate Cancer Progression
- Cancer type-specific profiling of chromatin regulator mutations identifies recurrent and co-occurring gene sets associated with improved survival following immune checkpoint therapy
- High-throughput protein interactome identifies LSD1 as a regulator of SARS-CoV-2 production through lysine demethylation of viral nucleocapsid protein
- CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction
BibTeX
@article{zanden2026genomewide,
title = {{Genome-wide CRISPR-screening identifies p53 as regulator of cancer cell sensitivity to the histone evicting anthracycline aclarubicin.}},
author = {Sabina Y van der Zanden and Koen Schipper and Merle A van Gelder and Amina Teunisse and Jay Sarthy and Aart G Jochemsen and Ruud H M Wijdeven and Jacques Neefjes},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09138-6},
url = {https://europepmc.org/article/MED/42971950},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genome-wide CRISPR-screening identifies p53 as regulator of cancer cell sensitivity to the histone evicting anthracycline aclarubicin.
AU - Sabina Y van der Zanden
AU - Koen Schipper
AU - Merle A van Gelder
AU - Amina Teunisse
AU - Jay Sarthy
AU - Aart G Jochemsen
AU - Ruud H M Wijdeven
AU - Jacques Neefjes
PY - 2026
DA - 2026/08/05
JO - Cell death & disease
DO - 10.1038/s41419-026-09138-6
UR - https://europepmc.org/article/MED/42971950
AB - 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.
SN - 2041-4889
ER -