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PARP1 suppression drives ROS resistance in aneuploid cancer cells.
Pan Cheng1, Angela Mermerian-Baghdassarian1, Yufeng Wang1
1Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA; Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA.
Molecular Cell
|May 1, 2026
Summary
Aneuploidy, an abnormal chromosome number, enhances cancer cell survival by suppressing poly(ADP-ribose) polymerase 1 (PARP1) and resisting reactive oxygen species (ROS) damage. This mechanism promotes tumor progression and metastasis.
Area of Science:
- Cancer Biology
- Genetics
- Cellular Mechanisms
Background:
- Aneuploidy is prevalent in cancer and linked to tumor progression.
- Mechanisms driving aneuploidy's role in cancer remain unclear.
- Reactive oxygen species (ROS) are implicated in cancer cell death pathways.
Purpose of the Study:
- To elucidate the mechanisms by which aneuploidy influences cancer progression.
- To investigate the role of ROS resistance in aneuploid cancer cells.
- To identify molecular players mediating aneuploidy's effects on cell death and metastasis.
Main Methods:
- Generation of aneuploid cell models.
- Assessment of ROS resistance and cell death pathways.
- Analysis of poly(ADP-ribose) polymerase 1 (PARP1) expression and function.
- Genome-wide CRISPR screening.
- Validation in human tumor samples.
Main Results:
- Aneuploidy confers resistance to ROS-mediated cell death, independent of specific chromosomal changes.
- PARP1 is suppressed in aneuploid cells, inhibiting PARP1-mediated cell death (parthanatos).
- PARP1 downregulation correlates with tumor metastasis, while upregulation suppresses it.
- CCAAT/enhancer-binding protein beta (CEBPB) mediates PARP1 suppression and ROS resistance in aneuploid cells, activated by lysosomal dysfunction.
Conclusions:
- Aneuploidy promotes cancer progression by suppressing PARP1 via CEBPB activation.
- This pathway confers ROS resistance, contributing to tumor aggressiveness.
- Targeting this mechanism could offer new therapeutic strategies for aneuploid cancers.
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