Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability
Open accessAbstract
Caspase-2 is an initiator caspase, which has been implicated to function in apoptotic and non-apoptotic signalling pathways, including cell-cycle regulation, DNA-damage signalling and tumour suppression. We previously demonstrated that caspase-2 deficiency enhances E1A/Ras oncogene-induced cell transformation and augments lymphomagenesis in the EμMyc mouse model. Caspase-2(-/-) mouse embryonic fibroblasts (casp2(-/-) MEFs) show aberrant cell-cycle checkpoint regulation and a defective apoptotic response following DNA damage. Disruption of cell-cycle checkpoints often leads to genomic instability (GIN), which is a common phenotype of cancer cells and can contribute to cellular transformation. Here we show that caspase-2 deficiency results in increased DNA damage and GIN in proliferating cells. Casp2(-/-) MEFs readily escape senescence in culture and exhibit increased micronuclei formation and sustained DNA damage during cell culture and following γ-irradiation. Metaphase analyses demonstrated that a lack of caspase-2 is associated with increased aneuploidy in both MEFs and in EμMyc lymphoma cells. In addition, casp2(-/-) MEFs and lymphoma cells exhibit significantly decreased telomere length. We also noted that loss of caspase-2 leads to defective p53-mediated signalling and decreased trans-activation of p53 target genes upon DNA damage. Our findings suggest that loss of caspase-2 serves as a key function in maintaining genomic integrity, during cell proliferation and following DNA damage.
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Casp2−/− mice accumulate aneuploid bone marrow cells with aging; Casp2−/− malignant cells have increased aneuploidy vs wild-type.
“In line with a key role for CASP2 in the control of mitotic proficiency, the bone marrow of Casp2−/− mice accumulates aneuploid cells with aging [985], and Casp2−/− malignant cells exhibit increased levels of aneuploidy as compared to their wild-type counterparts [982, 986, 987].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [987]
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نقش p53 در آپوپتوز و درمان سرطان
دلویی, م. ن., & زاده, ر. ع. (2014) · مجله علمی پژوهشی افق دانش
Role of p53 in Apoptosis and Cancer Therapy
Daloii, M. R. N., & Abdollahzade, R. (2014) · مجله علمی پژوهشی افق دانش
Characterisation of caspase-2 function in the DNA damage response and tumour suppression.
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Self-citationEvidence by interaction : a new role of caspase-2
Forsberg, J. (2018) · Figshare
- Authors
- Dorstyn, L., Puccini, J., Wilson, C. H., Shalini, S., Nicola, M., Moore, S., & Kumar, S.
- Affiliations
- South Australia Pathology (AU)
- Corresponding author
- Dorstyn, L
- Kumar, S
- Venue
- Cell Death & Differentiation
- Published
- 2012-04-13
- Volume
- 19
- Issue
- 8
- Pages
- 1288-1298
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3392630
- OpenAlex
- W1992486354
- Cited by
- 104
- References
- 41
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 13 · 2017: 11 · 2016: 9 · 2015: 4 · 2014: 15 · 2013: 10 · 2012: 2
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-07-09)
- Open access
- bronze
- doi.org
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Medical Research Council
- National Health and Medical Research Council (626905, 1002863)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- caspase-2, DNA damage response, genomic instability, cell cycle checkpoints, apoptosis, senescence escape, micronuclei, aneuploidy, telomere length, p53 pathway, gamma irradiation, mouse embryonic fibroblasts
- MeSH terms
- Aneuploidy, Animals, Cells, Cultured, Disease Models, Animal, DNA Damage, Embryo, Mammalian, Fibroblasts, Humans, Transfection, Signal Transduction, Mice, Knockout, Genomic Instability, Cell Growth Processes, Mice, Caspase 2
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