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Type: Journal article
Title: Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability
Author: Dorstyn, L.
Puccini, J.
Wilson, C.
Shalini, S.
Nicola, M.
Moore, S.
Kumar, S.
Citation: Cell Death and Differentiation, 2012; 19(8):1288-1298
Publisher: Nature Publishing Group
Issue Date: 2012
ISSN: 1350-9047
Statement of
L Dorstyn, J Puccini, CH Wilson, S Shalini, M Nicola, S Moore and S Kumar
Abstract: 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.
Keywords: Cells, Cultured
Mice, Knockout
DNA Damage
Disease Models, Animal
Genomic Instability
Signal Transduction
Cell Growth Processes
Caspase 2
Embryo, Mammalian
Rights: ©2012 Macmillan Publishers Limited. All rights reserved.
DOI: 10.1038/cdd.2012.36
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