Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability

L. Dorstyn, J. Puccini, M. Nicola, S. Moore, S. Kumar

Research output: Contribution to journalArticleResearchpeer-review

65 Citations (Scopus)

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 EMyc 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 EMyc 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.

Original languageEnglish
Pages (from-to)1288-1298
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number8
DOIs
Publication statusPublished - 1 Aug 2012
Externally publishedYes

Keywords

  • caspases
  • cell cycle
  • DNA-damage response
  • genomic instability

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