Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis.

Autor: Boice AG; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.; Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, 77030, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Lopez KE; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.; Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, 77030, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Pandita RK; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Texas A&M Institute of Biosciences and Technology, Houston, TX, 77030, USA., Parsons MJ; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA., Charendoff CI; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA.; Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, 77030, USA., Charaka V; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, 77030, USA., Carisey AF; Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, 77030, USA.; Department of Pediatrics, Section of Allergy and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA., Pandita TK; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Texas A&M Institute of Biosciences and Technology, Houston, TX, 77030, USA.; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, 77030, USA., Bouchier-Hayes L; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA. bouchier@bcm.edu.; Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, 77030, USA. bouchier@bcm.edu.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. bouchier@bcm.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Jan; Vol. 41 (2), pp. 204-219. Date of Electronic Publication: 2021 Oct 30.
DOI: 10.1038/s41388-021-02085-w
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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