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https://hdl.handle.net/2440/76298
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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 1476-5403 |
Statement of Responsibility: | 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 Fibroblasts Animals Mice, Knockout Humans Mice DNA Damage Disease Models, Animal Aneuploidy Genomic Instability Transfection Signal Transduction Cell Growth Processes Caspase 2 Embryo, Mammalian |
Rights: | ©2012 Macmillan Publishers Limited. All rights reserved. |
DOI: | 10.1038/cdd.2012.36 |
Published version: | http://dx.doi.org/10.1038/cdd.2012.36 |
Appears in Collections: | Aurora harvest Medicine publications |
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