In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.
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We would like to thank Jennifer Martinez (NIEHS) for careful reading of this paper. Funding for this project includes NIH/NIGMS R01GM121389 (LBH), NIH/NCI R21CA256606 (LBH) and NIH/NIGMS T32GM008231 (KEL). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of J. M. Sederstrom. We would like to acknowledge the Texas Children’s Hospital William T. Shearer Center for Human Immunobiology for their generous support for this research and the expert assistance of Rebecca Kairis.
MJP is currently employed at BD Biosciences. The remaining authors have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Boice, A.G., Lopez, K.E., Pandita, R.K. et al. Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis. Oncogene 41, 204–219 (2022). https://doi.org/10.1038/s41388-021-02085-w