title: Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability.
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.
authors.affiliation: Department of Haematology, Centre for Cancer Biology/SA Pathology, Adelaide, SA, Australia. Loretta.Dorstyn@health.sa.gov.au
authors.forename: L
authors.initials: L
authors.lastname: Dorstyn
authors.forename: J
authors.initials: J
authors.lastname: Puccini
authors.forename: C H
authors.initials: CH
authors.lastname: Wilson
authors.forename: S
authors.initials: S
authors.lastname: Shalini
authors.forename: M
authors.initials: M
authors.lastname: Nicola
authors.forename: S
authors.initials: S
authors.lastname: Moore
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000782:Aneuploidy; D000818:Animals; D053143:Caspase 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D014162:Transfection
chemical_list: D053143:Caspase 2