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dc.contributor.authorDorstyn, L.-
dc.contributor.authorPuccini, J.-
dc.contributor.authorWilson, C.-
dc.contributor.authorShalini, S.-
dc.contributor.authorNicola, M.-
dc.contributor.authorMoore, S.-
dc.contributor.authorKumar, S.-
dc.identifier.citationCell Death and Differentiation, 2012; 19(8):1288-1298-
dc.description.abstractCaspase-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.-
dc.description.statementofresponsibilityL Dorstyn, J Puccini, CH Wilson, S Shalini, M Nicola, S Moore and S Kumar-
dc.publisherNature Publishing Group-
dc.rights©2012 Macmillan Publishers Limited. All rights reserved.-
dc.subjectCells, Cultured-
dc.subjectMice, Knockout-
dc.subjectDNA Damage-
dc.subjectDisease Models, Animal-
dc.subjectGenomic Instability-
dc.subjectSignal Transduction-
dc.subjectCell Growth Processes-
dc.subjectCaspase 2-
dc.subjectEmbryo, Mammalian-
dc.titleCaspase-2 deficiency promotes aberrant DNA-damage response and genetic instability-
dc.typeJournal article-
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]-
Appears in Collections:Aurora harvest
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