p53-Independent Apoptosis Limits DNA Damage-Induced Aneuploidy

Abstract

DNA damage or unprotected telomeres can trigger apoptosis via signaling pathways that directly sense abnormal DNA structures and activate the p53 transcription factor. We describe a p53-independent mechanism that acts in parallel to the canonical DNA damage response pathway in Drosophila to induce apoptosis after exposure to ionizing radiation. Following recovery from damage-induced cell cycle arrest, p53 mutant cells activate the JNK pathway and expression of the pro-apoptotic gene hid. Mutations in grp, a cell cycle checkpoint gene, and puc, a negative regulator of the JNK pathway, sensitize p53 mutant cells to ionizing radiation (IR)-induced apoptosis. Induction of chromosome aberrations by DNA damage generates cells with segmental aneuploidy and heterozygous for mutations in ribosomal protein genes. p53-independent apoptosis limits the formation of these aneuploid cells following DNA damage. We propose that reduced copy number of haploinsufficient genes following chromosome damage activates apoptosis and helps maintain genomic integrity.

Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica

“…Secondly, it has been suggested that cell competition could be a mechanism to remove aneuploid cells. 27,28 As there is p53-independent removal of aneuploid cells, 27,28 our findings are consistent with cell competition as the mechanism.…”

“…[22][23][24][25][26] Cell competition may be a means to eliminate certain categories of aneuploid cells. 27,28 Seventy-nine ribosomal protein genes, sixty-six of which are haploinsufficient Minute loci, are distributed throughout the Drosophila genome. 2 Copy number changes to parts of the genome are likely to perturb relative dose of Rp/+ genes, and those that reduce Rp gene dose could be subject to cell competition.…”

“…This suggests cell competition can eliminate some aneuploid cells even after DNA damage responses have ceased. [27][28][29] In humans, heterozygosity for multiple different Rp mutations causes Diamond Blackfan Anemia. 30 Accumulation of ribosomal assembly intermediates or of unassembled ribosomal proteins in these genotypes activates p53, for example through the binding of the p53 ubiquitin ligase Mdm2 by RpL11 or RpL5.…”

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

“…In fact, it has been recently demonstrated that Dp53 and JNK establish a feedback loop that amplifies the initial apoptotic stimuli (Shlevkov and Morata, 2012). However, it has also been reported in a p53 mutant context that a p53-independent apoptosis mechanism is activated in response to ionising radiation and that this mechanism depends on the JNK pathway (McNamee and Brodsky, 2009). Based on these reports, we decided to analyse the effect of the depletion of JNK (basket in Drosophila) on apoptosis in wing discs that were also depleted of Dmp52 and Dp53.…”

In vitro cytotoxicity of SiO2 or ZnO nanoparticles with different sizes and surface charges on U373MG human glioblastoma cells

“…Other authors have suggested that, in addition to the ROS-mediated p53 activation pathway, SiO 2 and ZnO NPs may activate the p38 mitogen-activated protein kinase and/or c-Jun N-terminal kinase pathways to transactivate proapoptotic genes and induce apoptosis. 23,35 Since DNA damage induces the G 2 /M DNA damage checkpoint to arrest the cell cycle, 36 it is not surprising that silica NPs induce cell cycle arrest at the G 2 /M phase. 37 More specifically, they induce the G 2 /M DNA damage checkpoint via the activation of Chk1, which phosphorylates p53.…”